tbuckley/cabot-search huggingface dataset:
Calcium-channel blockade with nifedipine and angiotensin converting-enzyme inhibition with captopril in the therapy of patients with severe primary hypertension.
Authors: M D Guazzi, N De Cesare, C Galli, A Salvioni, C Tramontana, G Tamborini, A Bartorelli
Journal: Circulation (1984)

Nifedipine (10 mg qid) and captopril (25 mg qid) were tested alone and in combination in 14 patients suffering from severe primary hypertension. Each study period was of 1 week's duration. Circulatory response was evaluated through hourly pressure and pulse rate readings. The fall in pressure after oral nifedipine was maximal within 1 hr or less and was generally accompanied by palpitation and increase in pulse rate; with a six hourly dosing regimen the tendency of blood pressure to recover after each dose was interrupted by the next dose, so that values remained significantly reduced throughout the 24 hr, although pressure fluctuations were evident. Promptness of the antihypertensive action of captopril was similar, but the magnitude and the duration of the fall in pressure were less pronounced. When the converting-enzyme inhibitor was combined with the calcium-channel blocker, pressure fluctuations were not abolished, but the antihypertensive response was definitely enhanced, so that normal blood pressure was maintained for several hours during the day. Additional positive effects of captopril were mitigation of the heart rate reaction and prevention of the ankle pitting or edema elicited by nifedipine. A balance in arteriolar and venular dilatation promoted by captopril is the suggested mechanism for these effects. With the two-drug combination the function of the left ventricle was not reduced and possibly improved; blood urea nitrogen and serum electrolyte and creatinine concentration were not affected. Plasma renin activity increased with captopril and reverted toward baseline with the addition of nifedipine, suggesting an interference of the calcium-channel blocker with the release of renin.
P6 Menthol Has Beneficial Effects In The Airways Through A Trpm8-independent Mechanism
Authors: S. Maher, M. Birrell, S. Bonvini, M. Wortley, E. Dubuis, F. Shala, V. Jones, P. Flajolet, Y. Negreskul, Z. Britton, L. Hebib, M. Belvisi
Journal: Thorax (2014)

<h3>Introduction</h3> Asthma is a debilitating disease of the airways characterised by symptoms such as bronchoconstriction, hyperresponsiveness and cough. Current therapies are associated with significant side effects and are ineffective in severe disease highlighting the need for novel treatments. Menthol, a cooling compound found in medicinal products, is commonly thought to activate the thermo-sensing cation-permeable Transient Receptor Potential Melastatin 8 (TRPM8) channel. Furthermore, menthol is known for its beneficial effects in the airways such as bronchodilation<sup>1</sup> and suppression of nerve activation and cough,<sup>2</sup> however the mechanism of action is unknown. <h3>Aim</h3> To pharmacologically characterise the role of TRPM8 and menthol in the airways. <h3>Methods</h3> TRPM8 gene expression was measured using Taqman real-time PCR. Mouse and guinea pig isolated vagal nerves were mounted in a grease-gap chamber and depolarisation (mV) recorded as an indicator of sensory nerve activity. Segments of murine and guinea pig trachea were attached to a force transducer in an organ bath and relaxation of carbachol-induced tone recorded (mg). <h3>Results</h3> TRPM8 is expressed in mouse and guinea pig vagal ganglia. The selective TRPM8 agonist, WS3, caused activation of guinea pig and mouse isolated vagal nerves, which was inhibited by the TRPM8 antagonist, JNJ41876666. Furthermore, WS3-induced depolarisation was abolished in isolated vagal nerves from <i>Trpm8<sup>-/- </sup></i>mice. (-)-menthol (active form) caused a small depolarisation of mouse and guinea pig isolated vagal nerves, which was blocked by JNJ41876666. Interestingly, pre-incubation of (-)-menthol inhibited vagal nerve activation induced by the tussive stimulus, capsaicin, an effect that was not inhibited by JNJ41876666. WS3 and (-)-menthol caused a concentration-dependent relaxation of murine and guinea pig trachea, which was not abolished by JNJ41876666 nor in the <i>Trpm8</i><sup>-/-</sup> mouse airway. No expression of TRPM8 was detected in guinea pig or mouse airway smooth muscle. <h3>Conclusions</h3> (-)-menthol caused a small TRPM8-dependent activation but a robust TRPM8-independent inhibition of vagal sensory nerve activity and relaxation of airway smooth muscle. Elucidating the mechanism behind the beneficial effects of (-)-menthol could lead to the development of promising new therapeutic targets for airway diseases such as asthma. <h3>References</h3> Ito <i>et al.</i><i> Pulm Pharmacol Ther </i>2008;21(5):812–817 Plekova <i>et al.</i><i> J Appl Physiol </i>2013;115(2):268–274
Angiogenesis in the Bone Marrow of Patients with Breast Cancer
Authors: Mariana Chavez-MacGregor, Alejandro Aviles-Salas, Dan Green, Adolfo Fuentes-Alburo, Celedonio Gómez-Ruiz, Alvaro Aguayo
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Pathologic angiogenesis has been correlated with tumor growth, dissemination, metastasis, and prognosis in solid tumors including breast cancer. Angiogenesis has also been implicated in the pathophysiology of, and shown to be a therapeutic target in tumors arising in the bone marrow. The status of angiogenesis in the bone marrow of breast cancer patients is unknown. The aim of this study was to estimate the extent of bone marrow angiogenesis in this subset of patients. Experimental Design: We studied 42 women with breast cancer in whom a bone marrow biopsy was done. Bone marrow samples were sorted according to their infiltration status by breast cancer cells. In all bone marrow sections, blood vessels were highlighted by staining endothelial cells with an antibody directed against the CD34-related antigen. A hematopathologist blind to the status of infiltration of breast cancer did the bone marrow vessel count. Results: Nineteen patients (45%) had bone marrow metastasis. The bone marrow microvessel density was significantly higher in patients with bone marrow metastases compared with patients without bone marrow metastases (P &amp;lt; 0.0005). Median bone marrow microvessel density was 2 for the negative bone marrow group, and 15 for the positive bone marrow group. An increased microvessel density was correlated with presence of disease at last follow-up. Conclusions: This is the first study showing that bone marrow microvessel density is significantly higher in breast cancer patients with bone marrow metastases, when compared with breast cancer patients without evidence of bone marrow metastatic disease. Further research is needed to shed light into the prognostic and therapeutic relevance of this finding.
Adjuvant Tamoxifen Reduces Subsequent Breast Cancer in Women With Estrogen Receptor–Positive Ductal Carcinoma in Situ: A Study Based on NSABP Protocol B-24
Authors: D. Craig Allred, Stewart J. Anderson, Soonmyung Paik, D. Lawrence Wickerham, Iris D. Nagtegaal, Sandra M. Swain, Elefetherios P. Mamounas, Thomas B. Julian, Charles E. Geyer, Joseph P. Costantino, Stephanie R. Land, Norman Wolmark
Journal: Journal of Clinical Oncology (2012)

The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-24 study demonstrated significant benefit with adjuvant tamoxifen in patients with ductal carcinoma in situ (DCIS) after lumpectomy and radiation. Patients were enrolled without knowledge of hormone receptor status. The current study retrospectively evaluated the relationship between receptors and response to tamoxifen.Estrogen (ER) and progesterone receptors (PgR) were evaluated in 732 patients with DCIS (41% of original study population). An experienced central laboratory determined receptor status in all patient cases with available paraffin blocks (n = 449) by immunohistochemistry (IHC) using comprehensively validated assays. Results for additional patients (n = 283) determined by various methods (primarily IHC) were available from enrolling institutions. Combined results were evaluated for benefit of tamoxifen by receptor status at 10 years and overall follow-up (median, 14.5 years).ER was positive in 76% of patients. Patients with ER-positive DCIS treated with tamoxifen (v placebo) showed significant decreases in subsequent breast cancer at 10 years (hazard ratio [HR], 0.49; P < .001) and overall follow-up (HR, 0.60; P = .003), which remained significant in multivariable analysis (overall HR, 0.64; P = .003). Results were similar, but less significant, when subsequent ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately. No significant benefit was observed in ER-negative DCIS. PgR and either receptor were positive in 66% and 79% of patients, respectively, and in general, neither was more predictive than ER alone.Patients in NSABP B-24 with ER-positive DCIS receiving adjuvant tamoxifen after standard therapy showed significant reductions in subsequent breast cancer. The use of adjuvant tamoxifen should be considered for patients with DCIS.
Progression of Aortic Valve Calcification
Authors: Karsten Pohle, Ralph Mäffert, Dieter Ropers, Werner Moshage, Nicolaos Stilianakis, Werner G. Daniel, Stephan Achenbach
Journal: Circulation (2001)

Background Recent studies demonstrated an influence of atherosclerotic risk factors on the progression of aortic valve stenosis. The extent of aortic valve calcification (AVC) was also found to be a strong predictor of stenosis progression. We investigated the influence of the LDL cholesterol level (LDL), other standard cardiovascular risk factors, and the extent of coronary calcification (CC) on the progression of AVC quantified by electron beam tomography (EBT). Methods and Results In 104 patients (64.7±8 years, 89 male) with an EBT scan positive for AVC, CC and AVC were quantified using a volumetric score. EBT was repeated at a mean interval of 15 months (10 to 36 months), and the progression of AVC and CC was determined. Patients were divided into 2 groups according to LDL: group 1, LDL≤3.36 mmol/L (130 mg/dL), 57 patients; group 2, LDL&gt;3.36 mmol/L (130 mg/dL), 47 patients. Mean values for CC were 546±932 mm 3 in scan 1 and 665±1085 mm 3 in scan 2 for AVC 324±796 mm 3 and 404±1076 mm 3 , respectively. The mean progression of CC was 27±37% (group 1, 16±22%; group 2, 39±46%, P ≤0.001) and of AVC was 25±38% (group 1, 9±22%; group 2, 43±44%, P ≤0.001). Conclusions Quantification of AVC by EBT permits new insights into the progression of aortic valve sclerosis. We observed a strong influence of LDL cholesterol level on the progression of AVC and CC, suggesting that lipid-lowering therapy may decrease the progression of aortic valve calcification.
Chemotherapy with or without estrogenic recruitment in metastatic breast cancer. A randomized trial of the Gruppo Oncologico Nord Ovest (GONO)
Authors: P.F. Conte, E. Baldini, G. Gardin, P. Pronzato, D. Amadori, F. Carnino, C. Monzeglio, P. Gentilini, P. Gallotti, R. De Micheli, M. Venturini, A. Rubagotti, R. Rosso
Journal: Annals of Oncology (1996)
Heberden Oration, 1963 : The Epidemiology of Rheumatic Diseases
Authors: J. H. Kellgren
Journal: Annals of the Rheumatic Diseases (1964)

Fig. 2.-Radiographs of right hips and spine of daughter (a) and son (b) from family shown in Fig. 1.The second daughter has similar changes of intermediate severity.Both hips were affected in all three siblings.
Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis.
Authors: J Passwell, G F Schreiner, M Nonaka, H U Beuscher, H R Colten
Journal: Journal of Clinical Investigation (1988)

Systemic lupus erythematosus (SLE) is associated with the presence of complement proteins and immune complexes in affected organs. Since complement proteins are synthesized in hepatic and extrahepatic sites, we studied a murine model of SLE to ascertain the relative importance of local and humoral (liver) synthesis of complement. C3, C4, and C2 mRNA increase in kidney coincident with the development of nephritis in the MRL lpr/lpr mouse, a strain that spontaneously develops SLE. Two factor B messenger RNA transcripts are expressed in kidney and intestine; SLE nephritis is associated with decrease in the long factor B mRNA and increase in the short form. Increased local synthesis of C3 and B protein and a concomitant glomerular and renal interstitial macrophage infiltrate paralleled the increase in mRNA content in the (lpr/lpr) mice. In addition to kidney, an increase in C3, C4, C2 and factor B mRNA was noted in the lung, heart and intestine and to a lesser extent in liver of (lpr/lpr) in comparison to the MRL (+/+) animals. These results suggest that in SLE local expression of complement genes plays a role in the pathogenesis of chronic glomerulonephritis and in the autoimmune arteritis of other organs.
Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain
Authors: Matheus M de Gunst, Marielle I Gallegos-Ruiz, Giuseppe Giaccone, Jose Antonio Rodriguez
Journal: Molecular Cancer (2007)

Abstract Background The presence of EGFR kinase domain mutations in a subset of NSCLC patients correlates with the response to treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Although most EGFR mutations detected are short deletions in exon 19 or the L858R point mutation in exon 21, more than 75 different EGFR kinase domain residues have been reported to be altered in NSCLC patients. The phenotypical consequences of different EGFR mutations may vary dramatically, but the majority of uncommon EGFR mutations have never been functionally evaluated. Results We demonstrate that the relative kinase activity and erlotinib sensitivity of different EGFR mutants can be readily evaluated using transfection of an YFP-tagged fragment of the EGFR intracellular domain (YFP-EGFR-ICD), followed by immunofluorescence microscopy analysis. Using this assay, we show that the exon 20 insertions Ins770SVD and Ins774HV confer increased kinase activity, but no erlotinib sensitivity. We also show that, in contrast to the common L858R mutation, the uncommon exon 21 point mutations P848L and A859T appear to behave like functionally silent polymorphisms. Conclusion The ability to rapidly obtain functional information on EGFR variants of unknown relevance using the YFP-EGFR-ICD assay might prove important in the future for the management of NSCLC patients bearing uncommon EGFR mutations. In addition, our assay may be used to determine the response of resistant EGFR mutants to novel second-generation TKIs.
<i>In vivo</i> Effects of the Human Type I Insulin-Like Growth Factor Receptor Antibody A12 on Androgen-Dependent and Androgen-Independent Xenograft Human Prostate Tumors
Authors: Jennifer D. Wu, Austin Odman, Lily M. Higgins, Kathy Haugk, Robert Vessella, Dale L. Ludwig, Stephen R. Plymate
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The type I insulin-like growth factor receptor (IGF-IR) and its ligands have been shown to play a critical role in prostate carcinoma development, growth, and metastasis. Targeting the IGF-IR may be a potential treatment for prostate cancer. A fully human monoclonal antibody, A12, specific to IGF-IR, has shown potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo. In this study, we tested the in vivo effects of A12 on androgen-dependent and androgen-independent prostate tumor growth. Experimental Design: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively. When tumor volume reached about 150 to 200 mm3, A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks. Results: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G1 cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G2-M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgen-independent LuCaP 35V tumor cells. Conclusions: Our findings suggest that A12 is a therapeutic candidate for both androgen-dependent and androgen-independent prostate cancer. Our findings also suggest an IGF-IR–dependent activity of the androgen receptor in androgen-independent prostate cancer cells.
Pharmacological treatment of the biochemical defect in cystic fibrosis airways
Authors: H.C. Rodgers, A.J. Knox
Journal: European Respiratory Journal (2001)

The understanding of the biochemical defect in cystic fibrosis (CF) has advanced considerably since discovery of the CF gene in 1989 and characterization of its product. Studies showing that the abnormality in chloride flux could be corrected by transfection of wild-type cystic fibrosis transmembrane conductance regulator (CFTR) complimentary deoxyribonucleic acid (cDNA) have led to gene therapy trials on both sides of the Atlantic. However, gene therapy as a treatment for CF has yet to be realized. Pharmacological manipulation of the biochemical defect may provide an alternative or complementary approach to treatment. This review will discuss pharmacological agents in development which could correct the abnormal ion movement. The mechanisms of action of these pharmacological agents can be divided broadly into drugs which affect the most common CF mutation, ΔF508, which increase trafficking of the mutant CF protein to the apical membrane; drugs which increase chloride secretion; and drugs which reduce sodium reabsorption across the apical membrane. Treatment options for cystic fibrosis have developed rapidly since discovery of the cystic fibrosis gene over a decade ago. The targeting of specific therapies for particular cystic fibrosis genotypes and the use of combination treatments of chloride channel openers with sodium channel blockers are likely to be key advances in the next decade.
Combinations of Tumor and Treatment Parameters Are More Discriminative for Prognosis Than the Present TNM System in Rectal Cancer
Authors: Iris D. Nagtegaal, Marleen J.E.M. Gosens, Corrie A.M. Marijnen, Harm J. Rutten, Cornelis J.H. van de Velde, J. Han J.M. van Krieken
Journal: Journal of Clinical Oncology (2007)

Iris D. Nagtegaal and Marleen J.E.M. Gosens, Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands Corrie A.M. Marijnen, Department of Radiotherapy, Netherlands Cancer Institute, Amsterdam, the Netherlands Harm J. Rutten, Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands Cornelis J.H. van de Velde, Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands J. Han J.M. van Krieken, Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands
STUDIES ON THE EFFECT OF TRITON (WR-1339) ON GUINEA PIG TISSUES
Authors: Paul C. Hudgins, Robert A. Patnode
Journal: The Journal of Experimental Medicine (1958)

Guinea pig red cells exposed to triton WR-1339 either in vitro or in vivo demonstrate an increased sensitivity to hemolysis by thermal shock. Although the sensitivity of guinea pig leucocytes to thermal shock remains unchanged after a single injection of triton, their resistance to disruption by acetone and by sonic vibration is increased significantly. Resistance to sonic vibration appears to be maximum within a few hours after injection and then it gradually wanes. Paraffin oil-induced peritoneal exudate cells (monocytes) and leucocytes from whole blood are rendered more resistant to disruption by sonic vibration when exposed to triton in vitro. These findings are discussed briefly in relation to the therapeutic effect of triton in experimental tuberculosis.
Long-term use of ciclosporin in a real-world setting
Authors: J.I. Silverberg
Journal: British Journal of Dermatology (2015)

Journal Article Long‐term use of ciclosporin in a real‐world setting Get access J.I. Silverberg J.I. Silverberg Departments of Dermatology, Preventive Medicine and Medical Social Sciences Northwestern University Suite 1600, 676 N St Clair St Chicago IL 60611 U.S.ANorthwestern Medicine Multidisciplinary Eczema Center Chicago IL U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 172, Issue 6, 1 June 2015, Pages 1483–1484, https://doi.org/10.1111/bjd.13809 Published: 01 June 2015
A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation
Authors: Laurie L. Hill, Vijay K. Shreedhar, Margaret L. Kripke, Laurie B. Owen-Schaub
Journal: The Journal of Experimental Medicine (1999)

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.