tbuckley/cabot-search huggingface dataset:
Glucocorticoids for the treatment of anaphylaxis: Cochrane systematic review
Authors: K. J. L. Choo, E. Simons, A. Sheikh
Journal: Allergy (2010)

Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. A number of guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis.We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis.We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (Ovid) (1966 to September 2009), EMBASE (Ovid) (1988 to September 2009), CINAHL (EBSCOhost) (to September 2009) and The Science Citation Index Expanded (SCI-EXPANDED) (1945 to September 2009). We also searched the UK National Research Register and websites listing ongoing trials and contacted international experts in anaphylaxis in an attempt to locate unpublished material. We sought to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these). Two authors independently assessed articles for inclusion.None of the 2496 reports identified satisfied the inclusion criteria.We conclude that there is no evidence from high-quality studies for the use of steroids in the emergency management of anaphylaxis. Therefore, we can neither support nor refute the use of these drugs for this purpose.
ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES IN THE CLASSIFICATION OF VASCULITIS
Authors: John L. Niles, M.D
Journal: Annual Review of Medicine (1996)

▪ Abstract Two important types of antineutrophil cytoplasmic antibodies (ANCA) have been identified: anti-proteinase 3 and anti-myeloperoxidase antibodies. In the appropriate clinical setting, the presence of either is virtually diagnostic of the subset of vasculitis that includes Wegener's granulomatosis, microscopic polyangiitis (microscopic polyarteritis), the Churg-Strauss syndrome, idiopathic pauci-immune necrotizing and crescentic glomerulonephritis, and related and overlapping forms of these vasculitidies. The finding of ANCA throughout this group identifies these syndromes as belonging to a single category or spectrum of disease.
Human CD133 <sup>+</sup> Progenitor Cells Promote the Healing of Diabetic Ischemic Ulcers by Paracrine Stimulation of Angiogenesis and Activation of Wnt Signaling
Authors: Lucíola S. Barcelos, Cécile Duplaa, Nicolle Kränkel, Gallia Graiani, Gloria Invernici, Rajesh Katare, Mauro Siragusa, Marco Meloni, Ilaria Campesi, Manuela Monica, Andreas Simm, Paola Campagnolo, Giuseppe Mangialardi, Lara Stevanato, Giulio Alessandri, Costanza Emanueli, Paolo Madeddu
Journal: Circulation Research (2009)

We evaluated the healing potential of human fetal aorta-derived CD133 + progenitor cells and their conditioned medium (CD133 + CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2×10 4 CD133 + or CD133 − cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133 + cells expressed high levels of wingless ( Wnt ) genes, which were downregulated following differentiation into CD133 − cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133 + cells accelerated wound closure as compared with CD133 − or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133 + cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133 + CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by coadministering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133 + CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133 + CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133 + cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers.
Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes
Authors: Cristina Teodosio, Andrés C. García-Montero, María Jara-Acevedo, Laura Sánchez-Muñoz, Ivan Álvarez-Twose, Rosa Núñez, Lawrence B. Schwartz, Andrew F. Walls, Luis Escribano, Alberto Orfao
Journal: Journal of Allergy and Clinical Immunology (2010)
Inhibition of Integrin-Linked Kinase Attenuates Renal Interstitial Fibrosis
Authors: Yingjian Li, Xiaoyue Tan, Chunsun Dai, Donna B. Stolz, Dan Wang, Youhua Liu
Journal: Journal of the American Society of Nephrology (2009)

Integrin-linked kinase (ILK) is an intracellular serine/threonine protein kinase that regulates cell adhesion, survival, and epithelial-to-mesenchymal transition (EMT). In this study, we investigated the kinase activity of ILK during tubular EMT induced by TGF-beta1 and examined the therapeutic potential of an ILK inhibitor in obstructive nephropathy. TGF-beta1 induced a biphasic activation of ILK in renal tubular epithelial cells, with rapid activation starting at 5 min and the second wave of activation peaking at 24 h; the latter paralleled the induction of ILK protein expression. Pharmacologic inhibition of ILK with small-molecule inhibitor QLT-0267 abolished TGF-beta1-induced phosphorylation of Akt and glycogen synthase kinase-3beta, suppressed cyclin D1 expression, and largely restored the expression of E-cadherin and zonula occludens 1. Inhibition of ILK also blocked TGF-beta1-mediated induction of fibronectin, Snail1, plasminogen activator inhibitor 1, and matrix metalloproteinase 2. In a mouse model of obstructive nephropathy, administration of QLT-0267 inhibited beta-catenin accumulation; suppressed Snail1, alpha-smooth muscle actin, fibronectin, vimentin, and type I and type III collagen expression; and reduced total tissue collagen content. Inhibition of ILK did not affect kidney structure or function in normal mice. These findings suggest that increased ILK activity mediates EMT and the progression of renal fibrosis. Pharmacologic inhibition of ILK signaling may hold therapeutic potential for fibrotic kidney diseases.
Studies on Phenolic Steroids in Human Subjects. II. The Metabolic Fate and Hepato-Biliary-Enteric Circulation of C14-Estrone and C14-Estradiol in Women1
Authors: Avery A. Sandberg, W. Roy Slaunwhite
Journal: Journal of Clinical Investigation (1957)

One to two /sc. of 16-C1'-estrone (B1) or 16-CM-estra- diol-17,B (E2) 2 (both 1Elc.per 370 pg.) were injected 2C4.-estrone and C
Relationship between external resistances, lung function changes and maximal exercise capacity
Authors: CF Melissant, JW Lammers, M Demedts
Journal: European Respiratory Journal (1998)

In upper airway obstruction (UAO) the relationship between the degree of obstruction, exercise limitation and lung function indices is not well established. Therefore, we investigated in nine healthy subjects (age 36+/-9 yrs) the effects of two added resistances at the mouth (R1 = added resistance with 7.8 mm diameter; R2 = 5.7 mm) on forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), airway resistance (Raw) and maximal breathing capacity (measured during 15 s = measured maximum breathing capacity (MBCm); calculated as FEV1x37.5 = calculated maximum breathing capacity (MBCc)) on the one hand, and maximum exercise capacity (W'max), minute ventilation (V'E) and CO2 elimination (V'CO2) on the other. We found that R1 had almost no influence on FEV1 but decreased PEF by approximately 35% and increased Raw by almost 300%; it decreased W'max by merely approximately 10% while maximal exercise ventilation (V'Emax) was only 65% of control and only reached approximately 40% MBCc and approximately 70% MBCm; yet V'E and V'CO2 were significantly reduced at high exercise levels indicating hypoventilation. With R2, FEV1 was reduced by 25% and PEF by 55%, and Raw was increased by 600%; W'max was approximately 60% of control, V'Emax was only 35% of control and reached approximately 30% MBCc and approximately 60% MBCm, V'E was already reduced at moderate exercise levels. We conclude that: 1) an upper airway obstruction of 6 mm diameter (but not of 8 mm) had a marked influence on maximum exercise capacity due to hypoventilation; 2) calculated maximum breathing capacity markedly overestimated measured maximum breathing capacity because the forced expiratory volume in one second is an insensitive index of upper airway obstruction and because it does not take inspiratory flow limitation into account; and 3) a 10% decrease in maximum exercise capacity was linearly related with a 7% decrease in the forced expiratory volume in one second and a 150% increase in airway resistance. A 10% decrease in maximal exercise ventilation was related to a 8.5% decrease in peak expiratory flow and 9% decrease in measured maximum breathing capacity.
Silencing of Hypoxia Inducible Factor-1α by RNA Interference Attenuates Human Glioma Cell Growth<i>In vivo</i>
Authors: David L. Gillespie, Kum Whang, Brian T. Ragel, Jeannette R. Flynn, David A. Kelly, Randy L. Jensen
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Higher-grade gliomas are distinguished by increased vascular endothelial cell proliferation and peritumoral edema. These are thought to be instigated by vascular endothelial growth factor, which, in turn, is regulated by cellular oxygen tension. Hypoxia inducible factor-1α (HIF-1α) is a main responder to intracellular hypoxia and is overexpressed in many human cancers, including gliomas. Experimental Design: We investigated the role of HIF-1α in glioma growth in vivo using RNA interference (RNAi) in U251, U87, and U373 glioma cells. Results: We found that RNAi can be used to significantly attenuate glioma growth by reducing HIF-1α levels constitutively using short hairpin RNAs and transiently using small interfering RNAs (siRNA). HIF-1α levels on average were reduced 55% in normoxia and 71% in hypoxia. Vascular endothelial growth factor and GLUT-1 levels were reduced 81% and 71%, respectively, in the stable HIF-1α–reduced clones. These clones showed significant growth attenuation (up to 73%) compared with negative controls when grown in vivo in mouse flanks. Cellular proliferation was also reduced significantly, as determined by MIB-1 staining. Treating gliomas grown in mouse flank transiently with siRNA against HIF-1α by intratumoral injection resulted in a significant reduction of HIF-1α activity. This activity was followed using a hypoxia-responsive luciferase construct that enabled hypoxia imaging in vivo. Tumor volume in these siRNA injection experiments was reduced by 50% over the negative controls. Conclusions: These results indicate that transient RNAi directed against HIF-1α can effectively curb glioma growth in vivo.
Threshold Dose for Peanut: A Risk Characterization Based Upon DBPCFC of a Series of 287 Peanut-Allergic Individuals
Authors: D.A. Moneret-Vautrin, D. Sheffield, R.W.R. Crevel, M. Morisset, P. Dumont, S.L. Taylor
Journal: Journal of Allergy and Clinical Immunology (2009)
Serum Autoantibody Signature of Ductal Carcinoma <i>In Situ</i> Progression to Invasive Breast Cancer
Authors: Alain Mangé, Jérôme Lacombe, Caroline Bascoul-Mollevi, Marta Jarlier, Pierre-Jean Lamy, Philippe Rouanet, Thierry Maudelonde, Jérôme Solassol
Journal: Clinical Cancer Research (2012)

The identification of markers associated with progression to invasive breast cancer (IBC) is a major factor that can guide physicians in the initial therapeutic decision and the management of ductal carcinoma in situ (DCIS).We examined autoantibody targets in 20 DCIS and 20 IBC patients using protein microarrays and identified humoral responses that can be used to distinguish the two groups. The five most differentially targeted antigens were selected to generate an autoantibody signature for the in situ to invasive breast cancer transition. This signature was next tested on 120 independent samples (61 DCIS and 59 IBC) using specific ELISA assays. The prognosis value of the autoantibody signature was finally evaluated in a cohort of DCIS patients followed for 5 years.A set of five autoantibody targets (RBP-Jκ, HMGN1, PSRC1, CIRBP, and ECHDC1) with the highest differential signal intensity found in the protein microarrays experiment was used to establish an autoantibody signature of the DCIS to IBC transition. Using ELISA, this signature significantly discriminated DCIS from IBC [area under the ROC curve (AUC) = 0.794, 95% confidence interval (CI): 0.674-0.877]. Interestingly, our panel could highly distinguish low-grade DCIS from high-grade DCIS exhibiting an AUC of 0.749 (95% CI: 0.581-0.866). Finally, using a Kaplan-Meier analysis, the autoantibody signature could significantly divide the DCIS patients into a poor prognosis group and a good prognosis group (P = 0.01).These results indicate the potential of autoantibody detection as a new prognostic test with possible clinical implications for the management of DCIS.
Small molecule agents targeting the p53‐MDM2 pathway for cancer therapy
Authors: Weisi Wang, Yongzhou Hu
Journal: Medicinal Research Reviews (2011)

Abstract The powerful tumor suppressor p53 takes charge of a regulatory network to guard over the living cells from harmful effect of different forms of stress and eradicate the tumor cells for normal physiological condition maintenance. However the antitumor function of p53 is often attenuated or even omitted mainly due to two alternative mechanisms, direct gene alterations in p53 or negative controlled by MDM2 protein. In this article, overview on different therapeutic strategies that are exploited to restore the neoplasm therapeutic effect to p53 will be provided, including pharmacological rescue of mutant p53 and modulation of the p53‐MDM2 interaction. We attempt to focus on the medicinal chemistry aspects of small molecule agents targeting the p53‐MDM2 pathway and recent progress in these agents. In addition, the mechanism of action and anticancer activity of different classes of compounds targeting the p53‐MDM2 pathway, as well as structure–activity relationships, are discussed.
Randomized Biomarker Trial of Anastrozole or Low-Dose Tamoxifen or Their Combination in Subjects with Breast Intraepithelial Neoplasia
Authors: Bernardo Bonanni, Davide Serrano, Sara Gandini, Aliana Guerrieri-Gonzaga, Harriet Johansson, Debora Macis, Massimiliano Cazzaniga, Alberto Luini, Enrico Cassano, Sabina Oldani, Ernst A. Lien, Giuseppe Pelosi, Andrea Decensi
Journal: Clinical Cancer Research (2009)

Abstract Purpose: In the Anastrozole, Tamoxifen Alone or in Combination trial, the combination arm was inferior to anastrozole alone in terms of disease-free survival possibly due to an adverse pharmacokinetic interaction or a predominant estrogenic effect of tamoxifen under estrogen deprivation. We assessed whether the addition of a lower dose of tamoxifen influenced anastrozole bioavailability and favorably modulated biomarkers of bone fracture, breast cancer, cardiovascular disease, and endometrial cancer risk. The influence of CYP2D6 genotype on tamoxifen effects was also determined. Experimental Design: Seventy-five postmenopausal women with breast intraepithelial neoplasia were randomly allocated to either 1 mg/d anastrozole or 10 mg/wk tamoxifen or their combination for 12 months. Study endpoints were plasma drug concentrations and changes of C-telopeptide, osteocalcin, estradiol/sex hormone binding globulin (SHBG) ratio, estrone sulfate, insulin-like growth factor-I (IGF-I)/insulin-like growth factor binding protein-3 (IGFBP-3), C-reactive protein, antithrombin-III, endometrial Ki-67 expression, and thickness. Results: Anastrozole concentrations were not affected by the combination with low-dose tamoxifen, whereas endoxifen levels were lower in poor CYP2D6 metabolizers. C-telopeptide increased by 20 with anastrozole and decreased by 16 with tamoxifen and by 7 with their combination (P &amp;lt; 0.001); osteocalcin showed similar changes. Compared with anastrozole, the combination arm showed lower IGF-I/IGFBP-3 levels (17 versus 9; P = 0.004) and lower estradiol/SHBG and estrone sulfate reductions (15 versus 29 and 30 versus 38, respectively). However, IGF-I/IGFBP-3 and estradiol/SHBG did not decrease in poor CYP2D6 metabolizers. Endometrial thickness was not greater in the combination than in the anastrozole arm. Conclusions: The addition of a weekly tamoxifen administration did not impair anastrozole bioavailability and modulated favorably its safety profile, providing the rationale for further studies. (Clin Cancer Res 2009;15(22):705360)
Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation
Authors: Pedro Veliça, Mathias Zech, Sian Henson, Angelika Holler, Teresa Manzo, Rebecca Pike, Pedro Santos e Sousa, Lei Zhang, Bernhard Schiedlmeier, Martin Pule, Hans Stauss, Ronjon Chakraverty
Journal: Cancer Research (2015)

Abstract A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1low T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions. Cancer Res; 75(13); 2641–52. ©2015 AACR.
The impact of benzodiazepines on occurrence of pneumonia and mortality from pneumonia: a nested case-control and survival analysis in a population-based cohort
Authors: Eneanya Obiora, Richard Hubbard, Robert D Sanders, Puja R Myles
Journal: Thorax (2012)

<h3>Objectives</h3> Benzodiazepines have been associated with an increased incidence of infections, and mortality from sepsis, in the critically ill. Here, we determined the effect of community use of benzodiazepines on the occurrence of, and mortality following, pneumonia. <h3>Methods</h3> A nested case-control study using 29 697 controls and 4964 cases of community-acquired pneumonia (CAP) from The Health Improvement Network, a UK primary care patient database (2001–2002), investigated the association between benzodiazepines and pneumonia occurrence using conditional logistic regression. Cox regression was then used to determine the impact of benzodiazepines on mortality in the 4964 cases of CAP. Results are presented as adjusted OR, adjusted HR and 95% CI. <h3>Results</h3> Exposure to benzodiazepines was associated with an increased risk of pneumonia (OR 1.54, 95% CI 1.42 to 1.67). Individually diazepam, lorazepam and temazepam, but not chlordiazepoxide, were associated with an increased incidence of CAP. As a class, benzodiazepines were associated with increased 30-day (HR 1.22 (95% CI 1.06 to 1.39)) and long-term mortality (HR 1.32 (95% CI 1.19 to 1.47)) in patients with a prior diagnosis of CAP. Individually diazepam, chlordiazepoxide, lorazepam and temazepam affected long-term mortality in these patients. <h3>Conclusions</h3> Benzodiazepines were associated with an increased risk of, and mortality from, CAP. These hypothesis generating data suggest further research is required into the immune safety profile of benzodiazepines.
STUDIES OF COPROPORPHYRIN. III. IDIOPATHIC COPROPORPHYRINURIA; A HITHERTO UNRECOGNIZED FORM CHARACTERIZED BY LACK OF SYMPTOMS IN SPITE OF THE EXCRETION OF LARGE AMOUNTS OF COPROPORPHYRIN 1
Authors: Cecil James Watson, Samuel Schwartz, William Schulze, Leon O. Jacobson, Ralph Zagaria
Journal: Journal of Clinical Investigation (1949)
Mortality in Prostate Cancer and Use of Statins
Authors: Deniz Tural, Deniz Yuce, Saadettin Kilickap
Journal: Journal of Clinical Oncology (2014)

after diagnosis was associated with a decreased risk in prostate cancer and all-cause mortality. This effect was stronger in patients who also used statins before diagnosis, suggesting a possible effect of longer cumulative duration of use and higher cumulative doses. However, interpretation of this reason needs some consideration. The 2010 update of the staging system developed jointly by the American Joint Committee on Cancer and the International Union for Cancer Control is used for men with newly diagnosed prostate cancer. 2 This system combines information about the extent of the primary tumor, lymph node involvement, with the Gleason score of primary tumor and prostate specific antigen (PSA) level to classify men according to their risk of recurrence. However, in the Yu et al study,thereisnoavailableT-stageinformationforbothprediagnostic statin user and nonuser groups. In addition, the Gleason score of the primary tumor is not presented in 40.3% and 46.4% of patients with and without prediagnostic statin use, respectively. Concurrently, PSA levels at diagnosis are not presented in 21.9% and 29.9% of patients withandwithoutprediagnosticstatinuse,respectively.Thismayhave a bias effect on the outcome of their study.
TCT-130 FACTORS ASSOCIATED WITH LONG-TERM CARDIOVASCULAR EVENTS FOLLOWING ROTATIONAL ATHERECTOMY
Authors: Christos Eftychiou, David Barmby, Simon J. Wilson, Salahaddin Ubaid, Andrew J. Markwick, James C. Spratt, Mark Gunning, John Greenwood
Journal: Journal of the American College of Cardiology (2014)
Structure-Activity Relationships of Dopamine Agonists
Authors: J G Cannon
Journal: The Annual Review of Pharmacology and Toxicology (1983)

In the several years since Blaschko (1) suggested neurohormonal activity for dopamine, several types of chemical compounds have been found to possess dopamine-like actions. This review surveys classes of structures in which putative dopamine agonism has been reported, and cites struc­ ture-activity correlations. Detailed stereochemical aspects of dopamine ago­ nists have been addressed elsewhere (2). A serious problem in dopamine structure-activity studies arises from the large variety of animal models and in vivo and in vitro pharmacological assays utilized to assess dopaminergic effects. Comparable test data in the same animal species using the same biological endpoint and the same crite­ ria for assessment of activity/potency are not available for many agents. Thus, it is frequently not possible to make valid comparisons of actions and potencies among compounds described in the literature, and a caveat must be expressed with respect to the validity of many attempted structure­ activity correlations.