tbuckley/cabot-search huggingface dataset:
NEDD9 Depletion Destabilizes Aurora A Kinase and Heightens the Efficacy of Aurora A Inhibitors: Implications for Treatment of Metastatic Solid Tumors
Authors: Ryan J. Ice, Sarah L. McLaughlin, Ryan H. Livengood, Mark V. Culp, Erik R. Eddy, Alexey V. Ivanov, Elena N. Pugacheva
Journal: Cancer Research (2013)

Abstract Aurora A kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors have elevated levels of AURKA protein, few have AURKA gene amplification, implying that posttranscriptional mechanisms regulating AURKA protein levels are significant. Here, we show that NEDD9, a known activator of AURKA, is directly involved in AURKA stability. Analysis of a comprehensive breast cancer tissue microarray revealed a tight correlation between the expression of both proteins, significantly corresponding with increased prognostic value. A decrease in AURKA, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9. Reexpression of wild-type NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization, as mutation of S296E was sufficient to disrupt binding and led to reduced AURKA protein levels. NEDD9 confers AURKA stability by limiting the binding of the cdh1–substrate recognition subunit of APC/C ubiquitin ligase to AURKA. Depletion of NEDD9 in tumor cells increases sensitivity to AURKA inhibitors. Combination therapy with NEDD9 short hairpin RNAs and AURKA inhibitors impairs tumor growth and distant metastasis in mice harboring xenografts of breast tumors. Collectively, our findings provide rationale for the use of AURKA inhibitors in treatment of metastatic tumors and predict the sensitivity of the patients to AURKA inhibitors based on NEDD9 expression. Cancer Res; 73(10); 3168–80. ©2013 AACR.
Identification of Epidermal Growth Factor Receptor and c-erbB2 Pathway Inhibitors by Correlation With Gene Expression Patterns
Authors: K. Wosikowski, D. Schuurhuis, K. Johnson, S. E. Bates, K. D. Paull, T. G. Myers, J. N. Weinstein
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Growth factor receptor-signaling pathways are potentially important targets for anticancer therapy. The interaction of anticancer agents with specific molecular targets can be identified by correlating target expression patterns with cytotoxicity patterns. We sought to identify new agents that target and inhibit the activity of the epidermal growth factor (EGF) receptor and of c-erbB2 (also called HER2 or neu), by correlating EGF receptor, transforming growth factor (TGF)-α (a ligand for EGF receptor), and c-erbB2 messenger RNA (mRNA) expression levels with the results of cytotoxicity assays of the 49 000 compounds in the National Cancer Institute (NCI) drug screen database. Methods: The levels of mRNAs were measured and used to generate a molecular target database for the 60 cell lines of the NCI anticancer drug screen. The computer analysis program, COMPARE, was used to search for cytotoxicity patterns in the NCI drug screen database that were highly correlated with EGF receptor, TGF-α, or c-erbB2 mRNA expression patterns. The putative EGF receptor-inhibiting compounds were tested for effects on basal tyrosine phosphorylation, in vitro EGF receptor tyrosine kinase activity, and EGF-dependent growth. Putative ErbB2-inhibiting compounds were tested for effects on antibody-induced ErbB2 tyrosine kinase activity. Results: EGF receptor mRNA and TGF-α mRNA levels were highest in cell lines derived from renal cancers, and c-erbB2 mRNA levels were highest in cells derived from breast, ovarian, and colon cancers. Twenty-five compounds with high correlation coefficients (for cytotoxicity and levels of the measured mRNAs) were tested as inhibitors of the EGF receptor or c-erbB2 signaling pathways; 14 compounds were identified as inhibitors of these pathways. The most potent compound, B4, inhibited autophosphorylation (which occurs following activation) of ErbB2 by 50% in whole cells at 7.7 µM. Conclusions: Novel EGF receptor or c-erbB2 pathway inhibitors can be identified in the NCI drug screen by correlation of cytotoxicity patterns with EGF receptor or c-erbB2 mRNA expression levels.
Imatinib Mesylate Induces Cisplatin Hypersensitivity in Bcr-Abl+ Cells by Differential Modulation of p53 Transcriptional and Proapoptotic Activity
Authors: Ioanna Skorta, Moshe Oren, Christiane Markwardt, Matthias Gutekunst, Walter E. Aulitzky, Heiko van der Kuip
Journal: Cancer Research (2009)

Imatinib is highly effective in inducing remission in chronic myelogenous leukemia (CML). However, complete eradication of the malignant clone by imatinib is rare. We investigated the efficacy of combining imatinib with cisplatin. Inhibition of Bcr-Abl by imatinib induced a hypersensitive phenotype both in Bcr-Abl(+) cell lines and in CD34(+) cells from CML patients. Importantly, cisplatin sensitivity of leukemic cells harboring an inactive Bcr-Abl greatly exceeded that of Bcr-Abl(-) parental cells. The cisplatin response of Bcr-Abl(+) cells treated with imatinib was characterized by an impaired G(2)-M arrest and by rapid induction of mitochondrial cell death after the first passage through G(2). Imatinib abrogated ATM activation on cisplatin selectively in Bcr-Abl(+) cells. As a consequence, phosphorylation of p53 on Ser(15) and its activity as a transcription factor was significantly diminished. Furthermore, p53 accumulated predominantly in the cytoplasm in Bcr-Abl(+) cells treated with imatinib and cisplatin. Silencing of p53 significantly reduced sensitivity to cisplatin in imatinib-treated Bcr-Abl(+) cells, indicating that p53 retains its proapoptotic activity. Simultaneous downregulation of Bcl-x(L) was an additional requirement for cisplatin hypersensitivity, as p53-dependent cell death could be antagonized by exogenous Bcl-x(L). We conclude that imatinib sensitizes Bcr-Abl(+) cells to cisplatin by simultaneous inhibition of p53 transactivation, induction of p53 accumulation predominantly in the cytoplasm, and reduction of Bcl-x(L).
Physiology and Pharmacology of LHRH and Somatostatin
Authors: S M McCann
Journal: The Annual Review of Pharmacology and Toxicology (1982)

In this review I will try to give a brief account of the current status of two of the hypothalamic peptides which were characterized on the basis of their actions on the anterior pituitary gland. The literature on this subject is vast and this review will not list all of the pUblications. In a number of cases we will refer to previous recent reviews. Both of these peptides have now been shown to have a much wider spectrum of action than originally envisioned. Somatostatin acts as an inhibitory peptide in many bodily systems, whereas luteinizing hormone releasing hormone (LHRH) appears to have wide­ spread actions throughout the reproductive tract. For other references, the reader is referred to several excellent recent reviews (1-3).
Topical levocabastine protects better than sodium cromoglycate and placebo in conjunctival provocation tests
Authors: M. Rimaus, N.‐I. M. Kjellman, L.‐O. Blychert, B. Bjöurkstén
Journal: Allergy (1990)

Levocabastine is a new H 1 receptor blocking antihistamine which is intended for topical use in the treatment of allergic conjunctivitis. The protective effect of the drug in conjunctival provocation test (CPT) was evaluated in a double blind study of 25 children aged 9–17 years with confirmed pollen allergy. One drop of levocabastine, cromoglycate or placebo was instilled into the conjunctival sac of both eyes. After 15 min CPT was performed, starting with 320 BU of pollen extract. The allergen dose was increased every 10 min in half 10‐log steps in the right eye until a positive reaction occurred, or the top dose 320,000 BU was reached. The lowest dose resulting in a positive CPT reaction, i.e. at least 50% of the conjunctiva with erythema, was defined as the allergenic threshold dose (ATD). Pretreatment with levocabastine resulted in a median ATD of 32,000 BU, compared with 10,000 after cromoglycate ( p &lt;0.001) or placebo ( P &lt;0.01). Levocabastine was also superior in reducing subjective itch in the eyes. Determination of the ATD can be used as a relatively quick assessment of drugs intended for the treatment of allergic conjunctivitis.
Risk of chemotherapy-induced pulmonary fibrosis is associated with polymorphic tumour necrosis factor-a2 gene
Authors: J. Libura, F. Bettens, A. Radkowski, J.M. Tiercy, P.F. Piguet
Journal: European Respiratory Journal (2002)

In some patients, chemotherapy (CHT) of cancer can result in pulmonary inflammation and fibrosis, eventually leading to respiratory insufficiency. As animal studies have underlined the importance of major histocompatibility complex (MHC) genes in the susceptibility to bleomycin (BLM)-induced pulmonary fibrosis, the authors typed human leukocyte antigen-DR (HLA-DR) and tumor necrosis factor (TNF) genes in patients treated for Hodgkin's disease by a therapy including bleomycin. Patients were divided into pulmonary responders (PR) (n=21) or nonresponders (PNR) (n=20) on the basis of pulmonary alterations detected on chest radiography and the cumulated amount of BLM injected. The incidence of TNFa2, a microsatellite allele in the promoter region of the TNFB gene reported to be associated with increased TNF-a production, was significantly higher in PR than PNR (65% versus 19%). HLA-DRB1*15 showed a weak but nonsignificant association with the PR phenotype (50% versus 14%), as well as HLA-DRB1*03 (30% versus 19%) and TNFA-308*2 (30% versus 14%). TNFa2 and DR15 were independent risk factors and the occurrence of either genetic marker was 85% versus 29% in the PR and PNR groups respectively. Thus, the polymorphic TNFa2 microsatellite is associated with a risk of chemotherapy-induced pulmonary fibrosis.
The ability of synovitis to predict structural damage in rheumatoid arthritis: a comparative study between clinical examination and ultrasound
Authors: Maxime Dougados, Valérie Devauchelle-Pensec, Jean françois Ferlet, sandrine Jousse-Joulin, Maria-Antonietta D'Agostino, Marina Backhaus, Jacques Bentin, Gérard Chalès, Isabelle Chary-Valckenaere, Philip Conaghan, Richard J Wakefield, Frédéric Etcheparre, Philippe Gaudin, Walter Grassi, Désirée van der Heijde, Xavier Mariette, Esperanza Naredo, Marcin Szkudlarek
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To evaluate synovitis (clinical vs ultrasound (US)) to predict structural progression in rheumatoid arthritis (RA). <h3>Methods</h3> Patients with RA. <h3>Study design</h3> Prospective, 2-year follow-up. <h3>Data collected</h3> Synovitis (32 joints (2 wrists, 10 metacarpophalangeal, 10 proximal interphalangeal, 10 metatarsophalangeal)) at baseline and after 4 months of therapy by clinical, US grey scale (GS-US) and power doppler (PD-US); x-rays at baseline and at year 2. <h3>Analysis</h3> Measures of association (OR) were tested between structural deterioration and the presence of baseline synovitis, or its persistence, after 4 months of therapy using generalised estimating equation analysis. <h3>Results</h3> Structural deterioration was observed in 9% of the 1888 evaluated joints in 59 patients. Baseline synovitis increased the risk of structural progression: OR=2.01 (1.36–2.98) p&lt;0.001 versus 1.61 (1.06–2.45) p=0.026 versus 1.75 (1.18–2.58) p=0.005 for the clinical versus US-GS versus US-PD evaluation, respectively. In the joints with normal baseline examination (clinical or US), an increased probability for structural progression in the presence of synovitis for the other modality was also observed (OR=2.16 (1.16–4.02) p=0.015 and 3.50 (1.77–6.95) p&lt;0.001 for US-GS and US-PD and 2.79 (1.35–5.76) p=0.002) for clinical examination. Persistent (vs disappearance) synovitis after 4 months of therapy was also predictive of subsequent structural progression. <h3>Conclusions</h3> This study confirms the validity of synovitis for predicting subsequent structural deterioration irrespective of the modality of examination of joints, but also suggests that both clinical and ultrasonographic examinations may be relevant to optimally evaluate the risk of subsequent structural deterioration.
Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up
Authors: E S Molloy, C A Langford, T M Clark, C E Gota, G S Hoffman
Journal: Annals of the Rheumatic Diseases (2008)

To assess the efficacy of anti-tumour necrosis factor (TNF) therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies.Retrospective single-centre study of 25 patients with refractory TAK.Patients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months (range 2-84)) and 9 with ETA (median 28 months (range 4-82)); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in four patients that initially achieved stable remission. Four patients suffered adverse events, including one with opportunistic infections and one with breast cancer.In this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomised controlled trial of anti-TNF therapy in TAK.
Efficacy of the Novel Camptothecin Gimatecan against Orthotopic and Metastatic Human Tumor Xenograft Models
Authors: Michelandrea De Cesare, Graziella Pratesi, Silvia Veneroni, Raffaella Bergottini, Franco Zunino
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Gimatecan, a novel oral lipophilic camptothecin characterized by favorable features at molecular/cellular level and by a promising profile of preclinical activity, is currently in clinical phase I/II. The aim of the study was to additionally investigate the therapeutic potential of the drug in human tumor xenografts growing in different organs as models representative of tumor growth in the clinical setting. Experimental Design: The models include two orthotopic central nervous system tumors, two melanomas growing intracranially, and an ovarian carcinoma growing i.p. In addition, gimatecan was tested against experimental lung metastases of two tumor types (lung and ovarian carcinomas). Gimatecan was delivered by oral gavage according to various schedules (daily or intermittent). The time (in days) mice required to show evident signs of disease was used as end point for drug efficacy. Results: Gimatecan was highly effective in delaying disease manifestations in all tumor systems investigated. In the intracranially growing tumors, a significant time increase (versus control mice) was achieved by the drug administered according to all of the schedules. In addition, almost all treated mice were alive and tumor-free at the end of the experiment in the metastatic models and in the ascitic ovarian tumor. The daily prolonged treatment schedule was the best one. Conclusions: In all tumor systems investigated, including orthotopic tumor growth models and lung metastases, the oral administration of gimatecan showed a therapeutic benefit in terms of survival increase. The good oral availability allowed a prolonged daily treatment regimen, which seems the most promising to exploit the therapeutic potential of the drug.
Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells
Authors: Mary Jo Turk, José A. Guevara-Patiño, Gabrielle A. Rizzuto, Manuel E. Engelhorn, Alan N. Houghton
Journal: The Journal of Experimental Medicine (2004)

Concomitant tumor immunity describes immune responses in a host with a progressive tumor that rejects the same tumor at a remote site. In this work, concomitant tumor immunity was investigated in mice bearing poorly immunogenic B16 melanoma. Progression of B16 tumors did not spontaneously elicit concomitant immunity. However, depletion of CD4+ T cells in tumor-bearing mice resulted in CD8+ T cell–mediated rejection of challenge tumors given on day 6. Concomitant immunity was also elicited by treatment with cyclophosphamide or DTA-1 monoclonal antibody against the glucocorticoid-induced tumor necrosis factor receptor. Immunity elicited by B16 melanoma cross-reacted with a distinct syngeneic melanoma, but not with nonmelanoma tumors. Furthermore, CD8+ T cells from mice with concomitant immunity specifically responded to major histocompatibility complex class I–restricted epitopes of two melanocyte differentiation antigens. RAG1−/− mice adoptively transferred with CD8+ and CD4+ T cells lacking the CD4+CD25+ compartment mounted robust concomitant immunity, which was suppressed by readdition of CD4+CD25+ cells. Naturally occurring CD4+CD25+ T cells efficiently suppressed concomitant immunity mediated by previously activated CD8+ T cells, demonstrating that precursor regulatory T cells in naive hosts give rise to effective suppressors. These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor.
All-Cause Mortality After Diabetes-Related Amputation in Barbados
Authors: Ian R. Hambleton, Ramesh Jonnalagadda, Christopher R. Davis, Henry S. Fraser, Nish Chaturvedi, Anselm J. Hennis
Journal: Diabetes Care (2008)

OBJECTIVE—To determine the mortality rate after diabetes-related lower-extremity amputation (LEA) in an African-descent Caribbean population. RESEARCH DESIGN AND METHODS—We conducted a prospective case-control study. We recruited case subjects (with diabetes and LEA) and age-matched control subjects (with diabetes and no LEA) between 1999 and 2001. We followed these groups for 5 years to assess mortality risk and causes. RESULTS—There were 205 amputations (123 minor and 82 major). The 1-year and 5-year survival rates were 69 and 44% among case subjects and 97 and 82% among control subjects (case-control difference, P &amp;lt; 0.001). The mortality rates (per 1,000 person-years) were 273.9 (95% CI 207.1–362.3) after a major amputation, 113.4 (85.2–150.9) after a minor amputation, and 36.4 (25.6–51.8) among control subjects. Sepsis and cardiac disease were the most common causes of death. CONCLUSIONS—These mortality rates are the highest reported worldwide. Interventions to limit sepsis and complications from cardiac disease offer a huge potential for improving post-LEA survival in this vulnerable group.
[11] PHASE 2 STUDY OF OMEGA INTERFERON ALONE OR IN COMBINATION WITH RIBAVIRIN IN SUBJECTS WITH CHRONIC HEPATITIS C GENOTYPE-1 INFECTION
Authors: V. Novozhenov, N. Zakharova, E. Vinogradova, I. Nikitin, V. Gorbakov, A. Yakovlev, S. Pak, V. Rafalski, P. Bogomolov, T. Alessi, D. Blanche, W. Lang, P. Langecker, J. McNally, J. McHutchison
Journal: Journal of Hepatology (2007)
Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension
Authors: Kirsty M. Mair, Audrey F. Wright, Nicholas Duggan, David J. Rowlands, Martin J. Hussey, Sonia Roberts, Josephine Fullerton, Margaret Nilsen, Lynn Loughlin, Matthew Thomas, Margaret R. MacLean
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

The incidence of pulmonary arterial hypertension is greater in women, suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males, exogenously administered estrogen can protect against pulmonary hypertension (PH). However, in models that display female susceptibility, estrogens may play a causative role.To clarify the influence of endogenous estrogen and sex in PH and assess the therapeutic potential of a clinically available aromatase inhibitor.We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH: the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of sex on pulmonary expression of aromatase in these models and in lungs from patients with pulmonary arterial hypertension.Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was caused by reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor α also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased bone morphogenetic protein receptor 2 and Id1 expression compared with male. Anastrozole treatment reversed the impaired bone morphogenetic protein receptor 2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared with male.The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential.
H11 Kinase Is a Novel Mediator of Myocardial Hypertrophy In Vivo
Authors: Christophe Depre, Makoto Hase, Vinciane Gaussin, Anna Zajac, Li Wang, Luc Hittinger, Bijan Ghaleh, Xianzhong Yu, Raymond K. Kudej, Thomas Wagner, Junichi Sadoshima, Stephen F. Vatner
Journal: Circulation Research (2002)

By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy. Because this gene has not been characterized in the heart, the goal of the present study was to determine the function of H11 kinase in cardiac tissue, both in vitro and in vivo. In isolated neonatal rat cardiac myocytes, adenoviral-mediated overexpression of H11 kinase resulted in a 37% increase in protein/DNA ratio, reflecting hypertrophy. A cardiac-specific transgene driven by the alphaMHC-promoter was generated, which resulted in an average 7-fold increase in H11 kinase protein expression. Transgenic hearts were characterized by a 30% increase of the heart weight/body weight ratio, by the reexpression of a fetal gene program, and by concentric hypertrophy with preserved contractile function at echocardiography. This phenotype was accompanied by a dose-dependent activation of Akt/PKB and p70(S6) kinase, whereas the MAP kinase pathway was unaffected. Thus, H11 kinase represents a novel mediator of cardiac cell growth and hypertrophy.