tbuckley/cabot-search huggingface dataset:
Ca <sup>2+</sup> -Independent Activation of the Endothelial Nitric Oxide Synthase in Response to Tyrosine Phosphatase Inhibitors and Fluid Shear Stress
Authors: Ingrid Fleming, Johann Bauersachs, Beate Fisslthaler, Rudi Busse
Journal: Circulation Research (1998)

Abstract —Fluid shear stress enhances NO formation via a Ca 2+ -independent tyrosine kinase inhibitor–sensitive pathway. In the present study, we investigated the effects of the protein tyrosine phosphatase inhibitor phenylarsine oxide and of fluid shear stress on endothelial NO production as well as on the membrane association and phosphorylation of the NO synthase (NOS) III. Phenylarsine oxide (10 μmol/L) induced an immediate and maintained NO-mediated relaxation of isolated rabbit carotid arteries, which was insensitive to the removal of extracellular Ca 2+ and the calmodulin antagonist calmidazolium. This phenylarsine oxide–induced vasodilatation was unaffected by genistein but abrogated by the tyrosine kinase inhibitor erbstatin A. Incubation of native or cultured endothelial cells with phenylarsine oxide resulted in a time-dependent tyrosine phosphorylation of mainly Triton X-100–insoluble (cytoskeletal) proteins, along with a parallel change in the detergent solubility of NOS III, such that the enzyme was recovered in the cytoskeletal fraction. A similar, though slightly delayed, phenomenon was also observed after the application of fluid shear stress but not in response to any receptor-dependent agonist. Although Ca 2+ -independent NO formation was sensitive to erbstatin A, phenylarsine oxide treatment was associated with the tyrosine dephosphorylation of NOS III rather than its hyperphosphorylation. Proteins that also underwent redistribution in response to the tyrosine phosphatase inhibitor included paxillin, phospholipase C-γ 1 , mitogen-activated protein kinase, and the tyrosine kinases Src and Fyn. We envisage that fluid shear stress and tyrosine phosphatase inhibitors may alter the conformation and/or protein coupling of NOS III, facilitating its interaction with specific phospholipids, proteins, and/or protein kinases that enhance/maintain its Ca 2+ -independent activation.
Musculoskeletal manifestations in hyperlipidaemia: a controlled study.
Authors: P Klemp, A M Halland, F L Majoos, K Steyn
Journal: Annals of the Rheumatic Diseases (1993)

Eighty eight patients with hyperlipidaemia (81 white patients from South Africa and seven patients of mixed race from the West Cape area) were studied. Forty eight had adult familial hypercholesterolaemia, 16 had juvenile familial hypercholesterolaemia, and 24 had mixed hyperlipidaemia (increased cholesterol and triglycerides). They were interviewed and examined and their musculoskeletal manifestations compared with 88 controls with normal lipid profiles, and matched for age, sex, and race for each group of patients. The following manifestations were significantly increased in the patients: (a) tendon xanthomas particularly of the tendo Achillis in patients with adult familial hypercholesterolaemia and mixed hyperlipidaemia; (b) tendo Achillis tendinitis in patients with adult familial hypercholesterolaemia and mixed hyperlipidaemia; and (c) oligoarthritis in patients with mixed hyperlipidaemia but not in those with adult familial hypercholesterolaemia. Migratory polyarthritis and transient tendo Achillis pain were rare. Thirty eight per cent of patients with juvenile familial hypercholesterolaemia had musculoskeletal system manifestations none of which was significantly increased compared with controls. There was a significant association between tendon xanthomas and tendo Achillis tendinitis. There was a significant difference in pretreatment cholesterol levels in the patients with adult familial hypercholesterolaemia and musculoskeletal system manifestations compared with those without and in all three groups combined. The study confirms an association between hyperlipidaemia and tendon xanthomas, tendo Achillis tendinitis, and to a lesser extent oligoarthritis but not migratory polyarthritis or transient tendo Achillis pain as reported in other studies. It also shows that musculoskeletal system manifestations antedated the diagnosis of hyperlipidaemia in 24/39 (62%) patients and that the manifestations improved or resolved completely in 19/30 (63%) patients after receiving lipid lowering treatment. It is therefore important to recognise the association between musculoskeletal system manifestations and hyperlipidaemia for diagnostic and therapeutic reasons.
Cardiac and peripheral circulatory responses to angiotension and vasopressin in dogs.
Authors: R W Lee, S Standaert, L D Lancaster, D Buckley, S Goldman
Journal: Journal of Clinical Investigation (1988)

To determine the cardiac and peripheral circulatory responses to changes in afterload with angiotension and vasopressin, we increased mean aortic pressure 25% and 50% above control in splenectomized and ganglion-blocked dogs. We compared these responses to similar mechanical increases in aortic pressure produced by partial balloon occlusion of the descending aorta. With 25% or 50% increases in aortic pressure, angiotensin, vasopressin, and balloon inflation produced no changes in heart rate, right atrial, and mean pulmonary artery pressures. At 25% increase in aortic pressure, cardiac output was maintained with angiotensin and balloon occlusion but decreased with vasopressin. At 50% increase in aortic pressure, cardiac output was maintained with only balloon occlusion and decreased with both angiotensin and vasopressin. Whenever cardiac output fell, central blood volume did not increase as after-load increased. These changes in preload can be explained by alterations in the venous circulation. Vasopressin did not alter venous compliance or unstressed vascular volume but increased resistance to venous return. Angiotensin also increased resistance to venous return but decreased venous compliance and did not change unstressed vascular volume. Balloon occlusion had no effects on these parameters. We conclude that: (a) angiotensin caused significant venoconstriction resulting in maintenance of cardiac output at 25% but not 50% increase in aortic pressure; (b) vasopressin increased the resistance to venous return without venoconstriction; this resulted in a fall in cardiac output even with a 25% increase in aortic pressure; and (c) the effects of the agents on the venous circulation were independent of the mechanical effects of a pressure increase in the arterial circulation.
Kupffer cells modulate splenic interleukin-10 production in endotoxin-induced liver injury after partial hepatectomy
Authors: Kiyotaka Kurachi, Shohachi Suzuki, Takanori Sakaguchi, Yoshihiro Yokoi, Hiroyuki Konno, Satoshi Baba, Satoshi Nakamura
Journal: Journal of Hepatology (2003)
An Initial Report of a Radiation Dose-Escalation Trial in Patients with One to Five Sites of Metastatic Disease
Authors: Joseph K. Salama, Steven J. Chmura, Neil Mehta, Kamil M. Yenice, Walter M. Stadler, Everett E. Vokes, Daniel J. Haraf, Samuel Hellman, Ralph R. Weichselbaum
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Previous investigations have suggested that a subset of patients with metastatic cancer in a limited number of organs may benefit from local treatment. We investigated whether cancer patients with limited sites of metastatic disease (oligometastasis) who failed standard therapies could be identified and safely treated at one to five known sites of low-volume disease with radiotherapy. Experimental Design: Patients with one to five sites of metastatic cancer with a life expectancy of &amp;gt;3 months and good performance status received escalating doses of radiation to all known sites of cancer with hypofractionated radiation therapy. Patients were followed radiographically with computed tomography scans of the chest, abdomen, and pelvis and metabolically with [18F]fluorodeoxyglucose-positron emission tomography 1 month following treatment and then every 3 months. Acute toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. Results: Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade ≥3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients. Conclusions: Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.
Three cases of multiple basal cell carcinoma arising in port-wine stains previously treated with thorium X
Authors: M. Shah, F.M. Lewis, I.R. Palmer
Journal: British Journal of Dermatology (1996)

Journal Article Three cases of multiple basal cell carcinoma arising in port‐wine stains previously treated with thorium X Get access M. Shah, M. Shah Department of Dermatology, University Royal Hallamshire Hospital, Sheffield S10 2JF, U.K. Search for other works by this author on: Oxford Academic Google Scholar F.M. Lewis, F.M. Lewis Department of Dermatology, University Royal Hallamshire Hospital, Sheffield S10 2JF, U.K. Search for other works by this author on: Oxford Academic Google Scholar I.R. Palmer I.R. Palmer Department of Pathology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 135, Issue 5, 1 November 1996, Pages 861–862, https://doi.org/10.1111/j.1365-2133.1996.tb03911.x Published: 01 November 1996
Intimal injury and regrowth in the rabbit aorta; medial smooth muscle cells as a source of neointima.
Authors: T H Spaet, M B Stemerman, F J Veith, I Lejnieks
Journal: Circulation Research (1975)

The present study was undertaken to determine the mechanism of neointima formation in rabbit arteries subjected to extensive endothelial desquamation. Endothelial cells were selectively removed from the abdominal aorta by passing an inflated balloon catheter through the vessel. The healing response was then studied serially for up to a week, when neointima formation had provided a virtually complete cover. In en face preparations, the early neointimal cells appeared in random locations; they did not develop in apposition to residual, healthy endothelium. The possibility of blood cell colonization was explored by inserting killed aortic homografts. Since these homografts showed neointima formation only close to the site of junction with the normal aorta and as a direct extension of healthy endothelium, the likelihood of significant blood cell colonization was deemed small. Histologic and electron microscopic sections provided evidence that the early neointimal cells in the healing aorta were derived from medial smooth muscle cells. Healing of the injured arterial intima was accompanied by thickening instead of prompt restoration to normal, and the thickened intima resembled an arteriosclerotic plaque. The present study thus supports the concept that arteriosclerosis is a disease involving proliferation of medial smooth muscle cells.
P260 Tiotropium Respimat(R) Add-on To Inhaled Corticosteroids Improves Lung Function In Patients With Symptomatic Mild Asthma: Results From A Phase Iii Trial
Authors: P. Paggiaro, D. Halpin, R. Buhl, M. Engel, V. Zubek, Z. Blahova, P. Moroni-Zentgraf, E. Pizzichini
Journal: Thorax (2014)

<h3>Background</h3> Despite currently available therapies and detailed guidelines, many people with mild asthma remain symptomatic; it is important to establish the efficacy and safety of new treatments in this group. <h3>Methods</h3> A Phase III, randomised, double-blind, parallel-group trial (GraziaTinA-asthma<sup>®</sup>; NCT01316380) evaluated the efficacy and safety of once-daily tiotropium 5 µg or 2.5 µg versus placebo (all delivered via the Respimat<sup>®</sup> SoftMist™ inhaler) for 12 weeks in patients with symptomatic asthma on low-dose inhaled corticosteroids (200–400 µg budesonide or equivalent). The primary end point was peak forced expiratory volume in 1 second (FEV<sub>1</sub>) within 3 h of dosing (0–3h) response (change from baseline) at 12 weeks. Secondary end points were trough FEV<sub>1</sub>, FEV<sub>1</sub> area under the curve (AUC)<sub>(0–3h)</sub> and peak expiratory flow responses (measured with the AM2+<sup>®</sup> device), and seven-question Asthma Control Questionnaire (ACQ-7) score. <h3>Results</h3> Of 464 treated patients, 155 received tiotropium Respimat<sup>®</sup> 5 µg, 154 received tiotropium Respimat<sup>®</sup> 2.5 µg and 155 received placebo Respimat<sup>®</sup>. Both tiotropium Respimat<sup>®</sup> doses were superior to placebo Respimat<sup>®</sup> in peak FEV<sub>1(0–3h)</sub> response (adjusted mean difference: 5 µg, 128 mL; 2.5 µg, 159 mL; both p &lt; 0.001) and trough FEV<sub>1</sub> response (adjusted mean difference: 5 µg, 122 mL, p = 0.001; 2.5 µg, 110 mL, p = 0.003). FEV<sub>1</sub> AUC<sub>(0–3h)</sub> response at each visit, versus placebo Respimat<sup>®</sup>, significantly favoured tiotropium Respimat<sup>®</sup> 5 µg (p = 0.009 to p &lt; 0.001) and 2.5 µg (all p &lt; 0.001, except Day 1). Adjusted mean morning and evening peak expiratory flow responses, versus placebo Respimat<sup>®</sup>, each week, all favoured tiotropium Respimat<sup>®</sup> 5 µg (all p &lt; 0.001) and 2.5 µg (all p &lt; 0.003). Adjusted mean ACQ­-7 score was similar across all arms (tiotropium Respimat<sup>®</sup> 5 µg, 1.391; tiotropium Respimat<sup>®</sup> 2.5 µg, 1.438; placebo Respimat<sup>®</sup>, 1.377). Adverse events were predominantly mild or moderate and were balanced between treatment groups. <h3>Conclusion</h3> Tiotropium Respimat<sup>®</sup> was effective and well tolerated in patients with symptomatic mild asthma despite low-dose inhaled corticosteroid treatment.
Detection of cross-reactive anti-DNA antibody idiotypes on renal tissue-bound immunoglobulins from lupus patients.
Authors: D A Isenberg, C Collins
Journal: Journal of Clinical Investigation (1985)

Cross-reactive anti-DNA antibody idiotypes have been identified on tissue-bound immunoglobulins in a study of renal biopsies from 26 systemic lupus erythematosus (SLE) patients. 12 (46%) biopsies were shown to have one or both the idiotypes tested for by anti-idiotypic reagents. The idiotypes were identified in the glomerular basement membrane, the mesangial cell cytoplasm, and in focal tuft proliferations. In contrast, in none of 24 immunoglobulin-positive disease control biopsies could either idiotype be demonstrated. Blocking studies in two patients indicated that the idiotypes were on anti-DNA antibodies. These findings indicate that some tissue-bound auto-antibodies are derived from related families of high-frequency germ line genes that are expressed in SLE patients. The potential role of anti-idiotypic therapy in SLE is discussed.
Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma
Authors: Barbara S. Paugh, Alberto Broniscer, Chunxu Qu, Claudia P. Miller, Junyuan Zhang, Ruth G. Tatevossian, James M. Olson, J. Russell Geyer, Susan N. Chi, Nasjla Saba da Silva, Arzu Onar-Thomas, Justin N. Baker, Amar Gajjar, David W. Ellison, Suzanne J. Baker
Journal: Journal of Clinical Oncology (2011)

Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG.Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas.Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar.DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.
SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress
Authors: Hyun-Seok Kim, Krish Patel, Kristi Muldoon-Jacobs, Kheem S. Bisht, Nukhet Aykin-Burns, J. Daniel Pennington, Riet van der Meer, Phuongmai Nguyen, Jason Savage, Kjerstin M. Owens, Athanassios Vassilopoulos, Ozkan Ozden, Seong-Hoon Park, Keshav K. Singh, Sarki A. Abdulkadir, Douglas R. Spitz, Chu-Xia Deng, David Gius
Journal: Cancer Cell (2010)
A STUDY OF MITOCHONDRIA IN EXPERIMENTAL POLIOMYELITIS
Authors: Gertrude Fisher McCann
Journal: The Journal of Experimental Medicine (1918)

Typical mitochondria can be found in the spinal ganglion cells of monkeys with experimental poliomyelitis, even when typical Nissl substance has disappeared, and mitochondria-like structures are found in the remaining protoplasm in the latest stage of neurophagocytosis.
World Food Programme seeks advice on improving safety of aid delivery
Authors: P. Moszynski
Journal: BMJ (2010)

Faced with a growing number of complex emergencies, where delivery of relief supplies is often challenging or dangerous, the World Food Programme has begun a wide ranging consultation with business, humanitarian, and military sectors to “tap leading-edge knowledge and technology on supply chain controls and risk management.”

The consultation is to ensure that aid can “more effectively and safely reach the hungriest people in natural disasters or in volatile environments such as Haiti, Afghanistan, and Somalia.”

“Every day we face severe dangers and obstacles as we seek to ensure food reaches the hungry safely and effectively,” said the programme’s executive director, Josette Sheeran. 

“I want to tap the …
Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery
Authors: Eric M. Pridgen, Frank Alexis, Timothy T. Kuo, Etgar Levy-Nissenbaum, Rohit Karnik, Richard S. Blumberg, Robert Langer, Omid C. Farokhzad
Journal: Science Translational Medicine (2013)

Nanoparticles targeted to the neonatal Fc receptor cross the intestinal epithelium and reach systemic circulation after oral administration.
Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas
Authors: Priscilla K Brastianos, Amaro Taylor-Weiner, Peter E Manley, Robert T Jones, Dora Dias-Santagata, Aaron R Thorner, Michael S Lawrence, Fausto J Rodriguez, Lindsay A Bernardo, Laura Schubert, Ashwini Sunkavalli, Nick Shillingford, Monica L Calicchio, Hart G W Lidov, Hala Taha, Maria Martinez-Lage, Mariarita Santi, Phillip B Storm, John Y K Lee, James N Palmer, Nithin D Adappa, R Michael Scott, Ian F Dunn, Edward R Laws, Chip Stewart, Keith L Ligon, Mai P Hoang, Paul Van Hummelen, William C Hahn, David N Louis, Adam C Resnick, Mark W Kieran, Gad Getz, Sandro Santagata
Journal: Nature Genetics (2014)
Effectiveness of temporary dose increase at recapturing response in patients on maintenance infliximab
Authors: P. Irving, M. Sastrillo, J. Duncan, S. Anderson, J. Sanderson
Journal: Gut (2011)

<h3>Introduction</h3> Biologic drugs are widely used in Crohn9s disease, often with good effect. Unfortunately, even with scheduled maintenance therapy, secondary loss of response is common affecting approximately 10–15% of patients/year. There are two main options for recapturing response; dose increase or interval reduction. Published data suggest that these strategies can recapture response in approximately 75% of patients. However, both of these strategies have cost implications. Anecdotal reports suggest that in patients losing response to regular infusions of infliximab (IFX) 5 mg/kg, a temporary increase to 10 mg/kg for two infusions can lead to subsequent recapture of response at 5 mg/kg. This strategy for dealing with loss of response to IFX was agreed with our PCTs and has been followed recently. The authors aimed to identify what proportion of patients were subsequently able to persist with IFX treatment at 5 mg/kg. <h3>Methods</h3> The authors performed a retrospective review of all patients with Crohn9s disease who had received double doses of IFX for loss of response since January 2009. Demographic data, HBI prior to the first infusion at the higher dose and prior to the first infusion at the lower dose, and ability to continue on IFX at 5 mg/kg were reviewed. <h3>Results</h3> To date, 18 patients (8M:10F, median age 32 (range 19–51)) have received double dose IFX for loss of response. Median disease duration was 5 years (range 1–40) and the median time to dose increase from starting IFX was 15 months (range 6–60). All had received standard induction doses of IFX at 5 mg/kg on weeks 0, 2 and 6 and were on scheduled maintenance therapy. The dose interval prior to dose increase was 8 weeks for 16 patients and 6 weeks for 2. 12 patients were on concurrent immunomodulators and 6 were not (4 – intolerance, 2 – patient choice). To date, full outcome data are available for 11 subjects. Dose increase was effective in most patients in the short term with the median HBI falling from 7 prior to the first infusion at 10 mg/kg, to 3.5 prior to the first infusion back at the standard dose (5 mg/kg). However, the majority (8/11) required transfer onto adalimumab. Six patients who swapped to adalimumab did so prior to, or after one reinfusion of standard dose IFX and two patients after two infusions. Of the three patients who were able to recapture response, two have had three infusions at 5 mg/kg and one patient has had seven. <h3>Conclusion</h3> There are clear drug cost advantages to temporary dose increase over permanent dose increase or interval reduction. However, this experience suggests that the ability to maintain patients on IFX using this strategy is likely inferior to permanent changes in dose or treatment interval.