tbuckley/cabot-search huggingface dataset:
A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene<i>CHOP</i>
Authors: Xiangjun Meng, Mili L. Leyva, Marjorie Jenny, Isabelle Gross, Samir Benosman, Bastien Fricker, Sébastien Harlepp, Pascal Hébraud, Anne Boos, Pauline Wlosik, Pierre Bischoff, Claude Sirlin, Michel Pfeffer, Jean-Philippe Loeffler, Christian Gaiddon
Journal: Cancer Research (2009)

Abstract Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other types of organometallic complexes, namely, some ruthenium-derived compounds (RDC), which would display cytotoxicity through different modes of action, might represent alternative therapeutic agents. We have studied both in vitro and in vivo the biological properties of RDC11, one of the most active compounds of a new class of RDCs that contain a covalent bond between the ruthenium atom and a carbon. We showed that RDC11 inhibited the growth of various tumors implanted in mice more efficiently than cisplatin. Importantly, in striking contrast with cisplatin, RDC11 did not cause severe side effects on the liver, kidneys, or the neuronal sensory system. We analyzed the mode of action of RDC11 and showed that RDC11 interacted poorly with DNA and induced only limited DNA damages compared with cisplatin, suggesting alternative transduction pathways. Indeed, we found that target genes of the endoplasmic reticulum stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in RDC11-treated cells. Induction of the transcription factor CHOP, a crucial mediator of endoplasmic reticulum stress apoptosis, was also confirmed in tumors treated with RDC11. Activation of CHOP led to the expression of several of its target genes, including proapoptotic genes. In addition, the silencing of CHOP by RNA interference significantly reduced the cytotoxicity of RDC11. Altogether, our results led us to conclude that RDC11 acts by an atypical pathway involving CHOP and endoplasmic reticulum stress, and thus might provide an interesting alternative for anticancer therapy. [Cancer Res 2009;69(13):5458–66]
Plasma Cytokine and Soluble Receptor Signature Predicts Outcome of Patients With Classical Hodgkin's Lymphoma: A Study From the Groupe d'Etude des Lymphomes de l'Adulte
Authors: René-Olivier Casasnovas, Nicolas Mounier, Pauline Brice, Marine Divine, Franck Morschhauser, Jean Gabarre, Jean-Yves Blay, Laurent Voillat, Pierre Lederlin, Aspasia Stamatoullas, Jacques Bienvenu, Michel Guiguet, Liliane Intrator, Monique Grandjean, Josette Brière, Christophe Ferme, Gilles Salles
Journal: Journal of Clinical Oncology (2007)

Approximately 15% of patients with localized and 30% with disseminated classical Hodgkin's lymphoma fail to respond or relapse after first-line treatment. Usual prognosis scoring systems are actually unable to identify this small subset of patients with good confidence, pointing out the need for additional prognostic biomarkers.We prospectively analyzed the prognosis value of plasma levels of tumor necrosis factor (TNF), its soluble receptors TNF-R1 and TNF-R2, IL-10, IL1-RA, IL-6, and soluble CD30 (sCD30) when taken before any treatment in 519 consecutive patients with a first diagnosis of classical Hodgkin's lymphoma.Levels of TNF higher than 46 pg/mL, TNF-R1 higher than 3 ng/mL, TNF-R2 higher than 5 ng/mL, IL-10 higher than 30 pg/mL, IL1-RA higher than 668 pg/mL, IL-6 higher than 30 pg/mL, and sCD30 higher than 80 U/mL were associated with poor event-free and overall survival. In multivariate analysis, high levels of IL1-RA, IL-6, and sCD30 were independent poor prognosis factors, and the cytokine signature based on their combination allowed the stratification of patients in four prognosis classes, reaching a 5-year event-free survival probability of 92%, 85%, 76%, and 15%, respectively. This index was more potent than other scoring systems to predict patient event-free survival, and remained independent from the international prognostic score (P < .001), adding significant prognostic information to its predictive power.Plasma cytokine signature is sufficient to predict disease-related outcome in classical Hodgkin's lymphoma, and allows the identification of patients with very high risk of treatment failure.
C-Reactive Protein and Risk of Lung Cancer
Authors: Anil K. Chaturvedi, Neil E. Caporaso, Hormuzd A. Katki, Hui-Lee Wong, Nilanjan Chatterjee, Sharon R. Pine, Stephen J. Chanock, James J. Goedert, Eric A. Engels
Journal: Journal of Clinical Oncology (2010)

Chronic inflammation could play a role in lung carcinogenesis, underscoring the potential for lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP, an inflammation biomarker) and CRP single nucleotide polymorphisms (SNPs) with prospective lung cancer risk.We conducted a nested case-control study of 592 lung cancer patients and 670 controls with available prediagnostic serum and 378 patients and 447 controls with DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 77,464). Controls were matched to patients on age, sex, entry year, follow-up time, and smoking. We measured CRP levels in baseline serum samples and genotyped five common CRP SNPs.Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR], 1.98; 95% CI, 1.35 to 2.89; P-trend < .001 for fourth quartile [Q4, > or = 5.6 mg/L] v Q1 [< 1.0 mg/L]). The CRP association did not differ significantly by histology, follow-up time, or smoking status, but was most apparent for squamous cell carcinomas (OR, 2.92; 95% CI, 1.30 to 6.54), 2 to 5 years before lung cancer diagnosis (OR, 2.33; 95% CI, 1.24 to 4.39), and among former smokers (OR, 2.48; 95% CI, 1.53 to 4.03) and current smokers (OR, 1.90; 95% CI, 1.06 to 3.41). Although CRP SNPs and haplotypes were associated with CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels among former smokers (Q4: 2.55%; 95% CI, 1.98% to 3.27% v Q1: 1.39%; 95% CI, 1.07% to 1.81%) and current smokers (Q4: 7.37%; 95% CI, 5.81% to 9.33% v Q1: 4.03%; 95% CI, 3.01% to 5.40%).Elevated CRP levels are associated with subsequently increased lung cancer risk, suggesting an etiologic role for chronic pulmonary inflammation in lung carcinogenesis.
Arterial Ultrastructure Influences Transport of Locally Delivered Drugs
Authors: Chao-Wei Hwang, Elazer R. Edelman
Journal: Circulation Research (2002)

An incomplete understanding of the transport forces and local tissue structures that modulate drug distribution has hampered local pharmacotherapies in many organ systems. These issues are especially relevant to arteries, where stent-based delivery allows fine control of locally directed drug release. Local delivery produces tremendous drug concentration gradients and although these are in part derived from transport forces, differences in deposition from tissue to tissue imply that tissue ultrastructure also plays an important role. We measured the equilibrium drug uptake and the penetration and diffusivity of dextrans (a model hydrophilic drug similar to heparin) and albumin in orthogonal planes in arteries explanted from different vascular beds. We found significant variations in drug distribution with geometric orientation and arterial connective tissue content. Drug diffusivities parallel to the connective tissue sheaths were one to two orders of magnitude greater than across these sheaths. This diffusivity difference remained relatively constant for drugs up to 70 kDa before decreasing for larger drugs. Drugs also distributed better into elastic arteries, especially at lower molecular weights, with almost 66% greater transfer into the thoracic aorta than into the carotid artery. Arterial drug transport is thus highly anisotropic and dependent on arterial tissue content. The role of the local composition and geometric organization of arterial tissue in influencing vascular pharmacokinetics is likely to become a critical consideration for local vascular drug delivery.
Endothelium-Dependent Flow-Mediated Vasodilation of Systemic Arteries Is Impaired in Patients With Myocardial Virus Persistence
Authors: Katja B. Vallbracht, Peter L. Schwimmbeck, Uwe Kühl, Bettina Seeberg, Heinz-Peter Schultheiss
Journal: Circulation (2004)

Myocardial virus persistence is frequently observed in patients with cardiomyopathy. Endothelial dysfunction in patients with cardiomyopathy is associated with inflammatory immunoresponses in myocardial biopsies. The aim of this study was to investigate the impact of myocardial virus persistence on endothelial function.In 124 patients with suspected cardiomyopathy, myocardial biopsies were examined for virus persistence (by polymerase chain reaction) and inflammation (by immunohistology). Endothelial function of the radial artery was examined by high-resolution ultrasound. Diameter changes in response to reactive hyperemia (flow-mediated dilation [FMD]) compared with glycerol trinitrate (GTN-MD) were measured. Mean age of the patients (55 men, 69 women) was 45+/-13 years; ejection fraction was 57+/-17%. In 73 patients, adenovirus, enterovirus, parvovirus, or HHV6 virus (V) was detected; in 51, no virus was detected. FMD was significantly impaired in patients with myocardial virus persistence compared with control subjects (Co): FMD-V, 3.38+/-2.67%; FMD-Co, 7.34+/-3.44 (P<0.001). In 86 patients, myocardial inflammation was confirmed (Inf). Of those, 57 had virus, and 29 did not. FMD was significantly impaired in patients with virus compared with controls: FMD-Inf-V, 3.24+/-2.66%; FMD-Inf-Co, 6.07+/-3.00 (P<0.001). In 38 patients, immunohistology of the myocardial biopsies was normal (Co); of those, 16 had virus, and 22 did not. FMD was impaired in patients with virus compared with control subjects: FMD-Co-V, 3.88+/-2.72%; FMD-Co-Co, 9.00+/-3.32% (P<0.001). Endothelium-independent vasodilation (GTN-MD) was not significantly affected.Myocardial virus persistence is associated with endothelial dysfunction. Endothelial dysfunction in patients with myocardial virus persistence can occur independently of endothelial activation or myocardial inflammation but is more pronounced in patients with concurrent inflammation.
Psychiatric Morbidity and Illness Experience of Primary Care Patients With Chronic Fatigue in Hong Kong
Authors: Sing Lee, Hong Yu, Yunkwok Wing, Cynthia Chan, Antoinette M. Lee, Dominic T.S. Lee, Char-nie Chen, Kehming Lin, Mitchell G. Weiss
Journal: American Journal of Psychiatry (2000)

The authors' goal was to examine the prevalence and experience of psychiatric morbidity among primary care patients with chronic fatigue in Hong Kong.One hundred adult patients with medically unexplained fatigue for 6 or more months were assessed with the Explanatory Model Interview Catalogue, psychopathological rating scales, and an enhanced version of the Structured Clinical Interview for DSM-III-R.The lifetime prevalence of DSM-III-R depressive and anxiety disorders was 54%. Current depressive and anxiety disorders were identified in 28 patients, who exhibited more psychopathology and functional impairment than other patients. Thirty-three patients had somatoform pain disorder, and 30 had undifferentiated somatoform disorder, but most of them could also be diagnosed as having shenjing shuairuo (weakness of nerves) and, to a lesser extent, ICD-10 neurasthenia. Chronic fatigue syndrome diagnosed according to the 1988 Centers for Disease Control criteria was rare (3%) and atypical. Generally, patients mentioned fatigue if asked, but pains (36%), insomnia (20%), and worries (13%) were the most troublesome symptoms. Most patients attributed illness onset to psychosocial sources.Psychiatric morbidity was common among primary care patients with chronic fatigue. Subthreshold psychiatric morbidity was very common and was more validly represented by the disease construct of shenjing shuairuo or neurasthenia than somatoform disorder.
Unavoidable mastectomy for ipsilateral breast tumour recurrence after conservative surgery: patient outcome
Authors: E. Botteri, N. Rotmensz, C. Sangalli, A. Toesca, N. Peradze, H.R. De Oliveira Filho, A. Sagona, M. Intra, P. Veronesi, V. Galimberti, A. Luini, U. Veronesi, O. Gentilini
Journal: Annals of Oncology (2009)
Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies
Authors: P. C. De Witt Hamer
Journal: Neuro-Oncology (2010)

The efficacy of small-molecule kinase inhibitors has recently changed standard clinical practice for several solid cancers. Glioblastoma is a solid cancer that universally recurs and unrelentingly results in death despite maximal surgery and radiotherapy with concomitant and adjuvant temozolomide. Several clinical studies using kinase inhibitors in glioblastoma have been reported. The present study systematically reviews the efficacy, toxicity, and tissue analysis of small-molecule kinase inhibitors in adult patients with glioblastoma as reported in published clinical studies and determines which kinases have been targeted by the inhibitors used in these studies. Publications were retrieved using a MEDLINE search and by screening meeting abstracts. A total of 60 studies qualified for inclusion, of which 25 were original reports. A total of 2385 glioblastoma patients receiving kinase inhibitors could be evaluated. The study designs included 2 phase III studies and 37 phase II studies. Extracted data included radiological response, progression-free survival, overall survival, toxicity, and biomarker analysis. The main findings were that (i) efficacy of small-molecule kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in standard clinical practice and (ii) 6 main kinase targets for inhibitors have been evaluated in these studies: EGFR, mTOR, KDR, FLT1, PKCβ, and PDGFR.
Milk Fat Globule EGF-8 Promotes Melanoma Progression through Coordinated Akt and Twist Signaling in the Tumor Microenvironment
Authors: Masahisa Jinushi, Yukoh Nakazaki, Daniel R. Carrasco, Dobrin Draganov, Nicholas Souders, Matthew Johnson, Martin C. Mihm, Glenn Dranoff
Journal: Cancer Research (2008)

Abstract The pathogenesis of malignant melanoma involves the interplay of tumor cells with normal host elements, but the underlying mechanisms are incompletely understood. Here, we show that milk fat globule EGF-8 (MFG-E8), a secreted protein expressed at high levels in the vertical growth phase of melanoma, promotes disease progression through coordinated αvβ3 integrin signaling in the tumor microenvironment. In a murine model of melanoma, MFG-E8 enhanced tumorigenicity and metastatic capacity through Akt-dependent and Twist-dependent pathways. MFG-E8 augmented melanoma cell resistance to apoptosis, triggered an epithelial-to-mesenchymal transition (EMT), and stimulated invasion and immune suppression. In human melanoma cells, MFG-E8 knockdown attenuated Akt and Twist signaling and thereby compromised tumor cell survival, EMT, and invasive ability. MFG-E8–deficient human melanoma cells also showed increased sensitivity to small molecule inhibitors of insulin-like growth factor I receptor and c-Met. Together, these findings delineate pleiotropic roles for MFG-E8 in the tumor microenvironment and raise the possibility that systemic MFG-E8 blockade might prove therapeutic for melanoma patients. [Cancer Res 2008;68(21):8889–98]
Crystal structure of a hypoallergenic isoform of the major birch pollen allergen Bet v 1 and its biological function
Authors: Zora Markovic-Housley, Massimo Degano, Doriano Lamba, Markus Susani, Fatima Ferreira, Otto Scheiner, Heimo Breiteneder
Journal: Journal of Allergy and Clinical Immunology (2002)
Immunocytochemical evidence for extra-cellular initiation of elastase-induced bronchial secretory cell metaplasia in hamsters
Authors: TG Christensen, PA Alonso
Journal: European Respiratory Journal (1996)

The bronchus is the only region of the hamster conducting airways to develop secretory cell metaplasia after an intratracheal instillation of human neutrophil elastase (HNE). We tested the hypothesis that this pathological change occurs because of cellular uptake of the enzyme that is specific to this region. HNE, dissolved in saline, was instilled into the trachea of hamsters, that were sacrificed 5, 15, 30 or 60 min later for immunocytochemical localization of the enzyme. Saline-treated animals served as controls. By light microscopy, HNE was evident only in the lumen and upon the epithelial surface in all airways, at all time points. Saline control tissues were negative. Electron microscopic immunogold staining revealed HNE within luminal macrophages and associated with mucus and, to a limited extent, upon the apical cell surface both in trachea and bronchus. A small amount of HNE staining occurred in the intercellular space and lamina propria of bronchi. Cytoplasmic gold particles were sparse both in treated and control animals. We conclude that instilled neutrophil elastase is excluded from the epithelial cytoplasm regardless of region. We thus reject the hypothesis of airway cellular uptake of HNE and suggest that stimulation of bronchial secretory cells to accumulate mucin granules is initiated at the cell surface, possibly by unmasking or altering region-specific receptors involved in signal transduction pathways governing mucin granule synthesis.
Epigenetic Control of Angiogenesis via DNA Methylation
Authors: Marcus P. Cooper, John F. Keaney
Journal: Circulation (2011)

some patients develop limb-and life-saving collat- erals but others do not constitutes one of the great challenges that face patients with peripheral vascular and coronary artery disease.A longstanding goal in vascular disease is the establishment of therapies that enhance angiogenesis in compromised tissue beds.To achieve this goal, however, it is essential to define and understand the underlying mechanisms that control angiogenesis and may distinguish individual patient capacity for collateral formation.In this issue of Circulation, Rao and colleagues 1 report that ischemic injury increases DNA methylation in several genes critical for angiogenesis.The methyl-CpG-binding domain 2 (MBD2) protein senses DNA methylation and mediates transcriptional repression of genes involved in angiogenesis and endothelial cell survival.This seminal report mechanistically links epigenetic changes in vascular cells to angiogenesis, paving the way for new therapies that could improve perfusion in patients with vascular disease.
Development of a simple prognostic nomogram for individualising 5-year and 10-year absolute risks of fracture: a population-based prospective study among postmenopausal women
Authors: T. A. C. M. van Geel, N. D. Nguyen, P. P. Geusens, J. R. Center, T. V. Nguyen, G.-J. Dinant, J. A. Eisman
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objectives</h3> Previous fracture prediction models have been based on the assumption of a stable risk of subsequent fractures over time. The aim of the present work was to develop a nomogram for prediction of 5-year and 10-year individualised absolute fracture risks for postmenopausal women taking into account the time relation between fractures. <h3>Methods</h3> A population-based prospective study was performed in 23 general practice centres located in the southern part of The Netherlands. At baseline (1992–1994), 4203 postmenopausal women between 50 and 80 years participated and 2372 of them also participated 10 years later. Baseline measurements included lumbar spine bone mineral density (BMD) and clinical risk factor evaluation. The incidence of fractures was ascertained. Bayesian model averaging and Cox9s proportional hazards model were used. <h3>Results</h3> After enrolment, 382 (16.1%) women had a clinical fracture. Fracture risk was associated with advancing age (HR 1.09 per SD (5 years); 95% CI 1.01 to 1.17), lumbar spine BMD (HR 1.23 per −1 SD; 95% CI 1.10 to 1.37) and a prior fracture, with HR 3.27 (95% CI 2.50 to 4.30) for a recent prior fracture (≤5 years previously) and HR 1.97 (95% CI 1.43 to 2.71) for a non-recent prior fracture after menopause (&gt;5 years previously). Women with a recent prior fracture had 66% higher risk of an incident fracture than those with a non-recent prior fracture (HR 1.66; 95% CI 1.15 to 2.40). <h3>Conclusions</h3> The nomogram developed can help doctors to inform patients more effectively and thus better manage patient care by providing an individualised fracture risk taking into account the time relationship for fractures.
Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial
Authors: Adèle Green, Gail Williams, Rachel Nèale, Veronica Hart, David Leslie, Peter Parsons, Geoffrey C Marks, Philip Gaffney, Diana Battistutta, Christine Frost, Carolyn Lang, Anne Russell
Journal: The Lancet (1999)
Post-irradiation morphoea
Authors: G.B. COLVER, A. RODGER, P.S. MORTIMER, J.A. SAVIN, S.M. NEILL, J.A.A. HUNTER
Journal: British Journal of Dermatology (1989)

Journal Article Post‐irradiation morphoea Get access G.B. COLVER, G.B. COLVER University Department of Dermatology, Royal Infirmary, Edinburgh U.K. Dr G.B. Colver, University Department of Dermatology, Royal Infirmary, Edinburgh EH3 9YW, U.K. Search for other works by this author on: Oxford Academic Google Scholar A. RODGER, A. RODGER Department of Radiation Oncology, Western General Hospital, Edinburgh U.K. Search for other works by this author on: Oxford Academic Google Scholar P.S. MORTIMER, P.S. MORTIMER Department of Dermatology, St. George's Hospital, Tooting U.K. Search for other works by this author on: Oxford Academic Google Scholar J.A. SAVIN, J.A. SAVIN University Department of Dermatology, Royal Infirmary, Edinburgh U.K. Search for other works by this author on: Oxford Academic Google Scholar S.M. NEILL, S.M. NEILL Department of Dermatology, Westminster Hospital, London U.K. Search for other works by this author on: Oxford Academic Google Scholar J.A.A. HUNTER J.A.A. HUNTER University Department of Dermatology, Royal Infirmary, Edinburgh U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 120, Issue 6, 1 June 1989, Pages 831–835, https://doi.org/10.1111/j.1365-2133.1989.tb01382.x Published: 01 June 1989
Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases.
Authors: N Seersholm, A Kok-Jensen, A Dirksen
Journal: Thorax (1994)

Previous estimates of the survival times of patients with alpha 1-antitrypsin deficiency have been based on selected patients.The survival times of 397 patients with severe alpha 1-antitrypsin deficiency identified by pulmonary impairment (index cases) or through family studies (non-index cases) were compared.The overall median survival time was 54.5 years with no significant difference between men and women. Survival for index cases was less than for the non-index cases regardless of smoking history (49.4 years and 69.3 years respectively). When index and non-index cases were analysed separately there was no difference between the survival of smokers and never smokers in the index group. In the non-index group smokers had a shorter survival time than never smokers. The survival time of never smokers was similar to that of the normal Danish population.The prognosis of severe alpha 1-antitrypsin deficiency is better than previously assumed and, although smoking is a major risk factor, the development of emphysema in patients with severe alpha 1-antitrypsin deficiency is multifactorial.