tbuckley/cabot-search huggingface dataset:
Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer
Authors: April A.N. Rose, Andrée-Anne Grosset, Zhifeng Dong, Caterina Russo, Patricia A. MacDonald, Nicholas R. Bertos, Yves St-Pierre, Ronit Simantov, Michael Hallett, Morag Park, Louis Gaboury, Peter M. Siegel
Journal: Clinical Cancer Research (2010)

Although the murine orthologue of glycoprotein nonmetastatic B (GPNMB), Osteoactivin, promotes breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer.The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB levels in several published gene expression data sets and two independent tissue microarrays derived from human breast tumors. GPNMB-expressing human breast cancer cell lines were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent.GPNMB expression correlates with shorter recurrence times and reduced overall survival of breast cancer patients. Epithelial-specific GPNMB staining is an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells and sensitizes them to killing by CDX-011 (glembatumumab vedotin), a GPNMB-targeted antibody-drug conjugate.GPNMB expression is associated with the basal/triple-negative subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic triple-negative breast cancers, a patient population that currently lacks targeted-therapy options.
Lead-Induced Downregulation of Soluble Guanylate Cyclase in Isolated Rat Aortic Segments Mediated by Reactive Oxygen Species and Cyclooxygenase-2
Authors: Elise Courtois, Maria Marques, Alberto Barrientos, Santos Casado, Antonio López-Farré
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Lead exposure is a known cause of hypertension. Although most studies have focused on lead-induced endothelial dysfunction and on the involvement of reactive oxygen species (ROS), it has been recently demonstrated that the vascular wall of lead-exposed rats has both an altered the endothelium-independent relaxing response and a reduced expression of soluble guanylate cyclase (sGC). The aim of the present study was to determine in in vitro incubated rat isolated aortic segments if lead downregulates sGC expression, analyzing the involvement of ROS and cyclooxygenase-2 (COX-2). The experiments were performed in isolated aortic segments from Wistar rats that were incubated with lead for 24 h. Lead significantly reduced sGC-β1 subunit expression in a concentration-dependent manner. The maximal reduction in sGC-β1 subunit expression was achieved with 1 ppm lead. Vitamin C (30 μmol/L) partially restored sGC-β1 subunit expression in lead (1 ppm)-exposed aortic segments. A similar protection of sGC-β1 subunit expression was obtained with both a protein kinase A inhibitor, H89 (1 μmol/L) and with rofecoxib (1 μmol/L), an inhibitor of COX-2 activity. Moreover, lead exposure increased COX-2 expression in the arterial wall. While vitamin C reduced both COX-2 expression and superoxide anion production related to lead exposure, rofecoxib failed to modify superoxide anion generation in lead-incubated aortic segments. In conclusion, the present results suggest the involvement of ROS and COX-2 in the downexpression of sGC-β1 subunit induced by lead in the rat vascular wall. E-mail: [email protected]
Complications of Right Heart Catheterization Procedures in Patients With Pulmonary Hypertension in Experienced Centers
Authors: Marius M. Hoeper, Stephen H. Lee, Robert Voswinckel, Massimiliano Palazzini, Xavier Jais, Alessandro Marinelli, Robyn J. Barst, Hossein A. Ghofrani, Zhi-Cheng Jing, Christian Opitz, Hans-Juergen Seyfarth, Michael Halank, Vallerie McLaughlin, Ronald J. Oudiz, Ralf Ewert, Heinrike Wilkens, Stefan Kluge, Hinrich-Cordt Bremer, Eva Baroke, Lewis J. Rubin
Journal: Journal of the American College of Cardiology (2006)
High mitochondria content is associated with prostate cancer disease progression
Authors: Katharina Grupp, Karolina Jedrzejewska, Maria Christina Tsourlakis, Christina Koop, Waldemar Wilczak, Meike Adam, Alexander Quaas, Guido Sauter, Ronald Simon, Jakob Robert Izbicki, Markus Graefen, Hartwig Huland, Thorsten Schlomm, Sarah Minner, Stefan Steurer
Journal: Molecular Cancer (2013)

Mitochondria are suggested to be important organelles for cancer initiation and promotion. This study was designed to evaluate the prognostic value of MTC02, a marker for mitochondrial content, in prostate cancer.Immunohistochemistry of using an antibody against MTC02 was performed on a tissue microarray (TMA) containing 11,152 prostate cancer specimens. Results were compared to histological phenotype, biochemical recurrence, ERG status and other genomic deletions by using our TMA attached molecular information.Tumor cells showed stronger MTC02 expression than normal prostate epithelium. MTC02 immunostaining was found in 96.5% of 8,412 analyzable prostate cancers, including 15.4% tumors with weak, 34.6% with moderate, and 46.5% with strong expression. MTC02 expression was associated with advanced pathological tumor stage, high Gleason score, nodal metastases (p < 0.0001 each), positive surgical margins (p = 0.0005), and early PSA recurrence (p < 0.0001) if all cancers were jointly analyzed. Tumors harboring ERG fusion showed higher expression levels than those without (p < 0.0001). In ERG negative prostate cancers, strong MTC02 immunostaining was linked to deletions of PTEN, 6q15, 5q21, and early biochemical recurrence (p < 0.0001 each). Moreover, multiple scenarios of multivariate analyses suggested an independent association of MTC02 with prognosis in preoperative settings.Our study demonstrates high-level MTC02 expression in ERG negative prostate cancers harboring deletions of PTEN, 6q15, and 5q21. Additionally, increased MTC02 expression is a strong predictor of poor clinical outcome in ERG negative cancers, highlighting a potentially important role of elevated mitochondrial content for prostate cancer cell biology.
Reduced Colitis-Associated Colon Cancer in<i>Fat-1</i>(<i>n</i>-3 Fatty Acid Desaturase) Transgenic Mice
Authors: Qian Jia, Joanne R. Lupton, Roger Smith, Brad R. Weeks, Evelyn Callaway, Laurie A. Davidson, Wooki Kim, Yang-Yi Fan, Peiying Yang, Robert A. Newman, Jing X. Kang, David N. McMurray, Robert S. Chapkin
Journal: Cancer Research (2008)

Abstract Bioactive food components containing n-3 polyunsaturated fatty acids (PUFA) modulate multiple determinants that link inflammation to cancer initiation and progression. Therefore, in this study, fat-1 transgenic mice, which convert endogenous n-6 PUFA to n-3 PUFA in multiple tissues, were injected with azoxymethane followed by three cycles of dextran sodium sulfate (DSS) to induce colitis-associated cancer. Fat-1 mice exhibited a reduced number of colonic adenocarcinomas per mouse (1.05 ± 0.29 versus 2.12 ± 0.51, P = 0.033), elevated apoptosis (P = 0.03), and a decrease in n-6 PUFA–derived eicosanoids, compared with wild-type (wt) mice. To determine whether the chemoprotective effects of n-3 PUFA could be attributed to its pleiotropic anti-inflammatory properties, colonic inflammation and injury scores were evaluated 5 days after DSS exposure followed by either a 3-day or 2-week recovery period. There was no effect of n-3 PUFA at 3 days. However, following a 2-week recovery period, colonic inflammation and ulceration scores returned to pretreatment levels compared with 3-day recovery only in fat-1 mice. For the purpose of examining the specific reactivity of lymphoid elements in the intestine, CD3+ T cells, CD4+ T helper cells, and macrophages from colonic lamina propria were quantified. Comparison of 3-day versus 2-week recovery time points revealed that fat-1 mice exhibited decreased (P &amp;lt; 0.05) CD3+, CD4+ T helper, and macrophage cell numbers per colon as compared with wt mice. These results suggest that the antitumorigenic effect of n-3 PUFA may be mediated, in part, via its anti-inflammatory properties. [Cancer Res 2008;68(10):3985–91]
The Evolutionary Origin and Genomic Organization of SINEs in Arabidopsis thaliana
Authors: Alain Lenoir, Laurence Lavie, José-Luis Prieto, Chantal Goubely, Jean-Charles Cote, Thierry Pélissier, Jean-Marc Deragon
Journal: Molecular Biology and Evolution (2001)

We have characterized the two families of SINE retroposons present in Arabidopsis thaliana. The origin, distribution, organization, and evolutionary history of RAthE1 and RAthE2 elements were studied and compared to the well-characterized SINE S1 element from Brassica. Our studies show that RAthE1, RAthE2, and S1 retroposons were generated independently from three different tRNAs. The RAthE1 and RAthE2 families are older than the S1 family and are present in all tested Cruciferae species. The evolutionary history of the RAthE1 family is unusual for SINEs. The 144 RAthE1 elements of the Arabidopsis genome cannot be classified in distinct subfamilies of different evolutionary ages as is the case for S1, RAthE2, and mammalian SINEs. Instead, most RAthE1 elements were probably derived steadily from a single source gene that was maintained intact and active for at least 12–20 Myr, a result suggesting that the RAthE1 source gene was under selection. The distribution of RAthE1 and RAthE2 elements on the Arabidopsis physical map was studied. We observed that, in contrast to other Arabidopsis transposable elements, SINEs are not concentrated in the heterochromatic regions. Instead, SINEs are grouped in the euchromatic chromosome territories several hundred kilobase pairs long. In these territories, SINE elements are closely associated with genes. A retroposition partnership between Arabidopsis SINEs and LINEs is proposed.
Lipoprotein e(P4) is essential for hemin uptake by Haemophilus influenzae.
Authors: J Reidl, J J Mekalanos
Journal: The Journal of Experimental Medicine (1996)

Heme uptake is a common means of iron and porphyrin acquisition by many pathogenic bacteria. The genus Haemophilus includes several important pathogenic bacterial species that characteristically require hemin-, protoporphyrin-, or heme-substituted proteins as essential growth factors under aerobic conditions. However, the mechanism of heme transport is not understood for Haemophilus. We have cloned a DNA fragment from H. influenzae that allows an Escherichia coli hemA mutant to employ exogenous hemin or protoporphyrin IX as sole sources of porphyrin. DNA sequencing of the cloned DNA fragment suggested that a previously characterized gene (hel) encoding an antigenic, outer membrane lipoprotein e(P4) was responsible for the complementation activity. Construction of hel insertion mutations in strain H. influenzae Rd demonstrated that hel is essential for growth under aerobic conditions but not under anaerobic conditions. The aerobic growth defect of hel mutants could be reversed by providing exogenous hemin in the presence of outer membrane. The analysis of hybrids between e(P4) and beta-lactamase demonstrated that a domain of e(P4) near its NH2' terminus was required for its function in hemin use. Within this domain is a short amino acid sequence that displays similarity to H. influenzae hemin binding protein HbpA, hemin-binding motifs present in eukaryotic transcription activator heme-activated protein, and the heme containing proteins hemoglobin (alpha-chain) and cytochrome C3, suggesting that this region may be involved in hemin binding and/or transport.
Studies of human sera with cytotoxic activity
Authors: Ralph C. Williams, Jean D. Emmons, Edmond J. Yunis
Journal: Journal of Clinical Investigation (1971)

42 human sera showing in vitro cytotoxic activity of restricted or broad HL-A specificities with test human lymphocytes were studied for the molecular and immunoglobulin class of cytotoxic antibody using sucrose gradient separations, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration. Sera originated from patients with previous multiple pregnancies (19), multiply transfused patients (8), subacute bacterial endocarditis (4), systemic lupus (2), and human umbilical cord sera (9). In 32 of 42 instances, predominant cytotoxic activity was found in high molecular weight gradient fractions; however, DEAE chromatographic separations revealed cytotoxic activity in initial buffer fractions containing primarily gammaG globulin. Gradient separations of cytotoxic activity within initial gammaG DEAE fractions showed localization of cytotoxicity only in high molecular weight materials. Confirmation of high molecular weight gammaG cytotoxic activity was obtained by resistance to mercaptoethanol treatment, abolition of activity after absorption only with specific anti-gammaG antisera, and by the finding that high molecular weight cytotoxic activity in gradients or gel filtration run at neutral pH 7.4 became 7S when separations were rerun at an acidic pH of 4.0. Such 7S activity again became rapidly sedimenting when the same fractions were again rerun in gradients at neutral pH.19S gammaM cytotoxic activity was documented in a panel of 15 human sera containing anti-"I" cold agglutinins. In this instance the cytotoxic activity appeared to be related to the cold agglutinin antibody since it was mercaptoethanol sensitive and could be demonstrated in monoclonal antibody eluates containing primarily gammaM. No in vitro protection again cytotoxic effect was demonstrated when isolated human 19S anti-gamma-globulins were aded to the lymphocytotoxic assay system. With the exception of cold agglutinins, human cytotoxic antibodies appear to be primarily gammaG producing in vitro lymphocyte killing either as 7S gammaG globulin or as rapidly sedimenting aggregates or complexes of gammaG molecules.
Interpreting the Economic Literature in Oncology
Authors: Patrick A. Grusenmeyer, Yu-Ning Wong
Journal: Journal of Clinical Oncology (2007)

New treatment options provide hope for patients with localized and advanced cancer. However, these advances are associated with cost, both in terms of treatment-related expenditures and effects on quality of life. It is important that patients, physicians, insurers, and policymakers understand the relationship between costs and outcomes of new cancer treatments. Various methods of cost analysis can provide a structured manner to assess cost. Cost-effectiveness analysis (CEA) compares the cost of the intervention with the effect, resulting in a cost per effect (eg, cost per year of life gained) that can be compared across interventions. In this article, we review three recent CEAs in the oncology literature, including chemoprevention in breast cancer, adjuvant endocrine therapy in early-stage breast cancer, and salvage chemotherapy in advanced ovarian cancer. The important elements of CEA, including the recommendations of the US Public Health Service Panel on Cost Effectiveness in Health and Medicine as they relate to cancer treatments, are discussed. Many well-done CEAs in cancer treatment have been performed during the last decade. As with clinical trials, the rigor and methods of the analysis are critical to the reliability of the results. Therapies with high cost and small incremental improvement in survival and/or quality of life may find it difficult to meet the societal thresholds for what is considered cost effective. CEA is a method to assess the cost and effect of cancer treatments, providing important insights into the best use (ie, obtaining the most value for) of health care expenditures. As the literature indicates, one must be cognizant of the fact that there can be extraordinary costs associated with some newer cancer therapies that provide small incremental clinical benefit. Better understanding of the cancer economic literature can help lead to an informed dialogue on the health policy implications of resource allocation in cancer care.
Focal Atrial Tachycardia
Authors: Satoshi Higa, Ching-Tai Tai, Yenn-Jiang Lin, Tu-Ying Liu, Pi-Chang Lee, Jin-Long Huang, Ming-Hsiung Hsieh, Yoga Yuniadi, Bien-Hsien Huang, Shih-Huang Lee, Kwo-Chang Ueng, Yu-An Ding, Shih-Ann Chen
Journal: Circulation (2003)

This study investigated the electrophysiologic characteristics, atrial activation pattern, and effects of radiofrequency (RF) catheter ablation guided by noncontact mapping system in patients with focal atrial tachycardia (AT).In 13 patients with 14 focal ATs, noncontact mapping system was used to map and guide ablation of AT. AT origins were in the crista terminalis (n=8), right atrial (RA) free wall (n=3), Koch triangle (n=1), anterior portion of RA-inferior vena cava junction (n=1), and superior portion of tricuspid annulus (n=1); breakout sites were in the crista terminalis (n=5), RA free wall (n=5), middle cavotricuspid isthmus (n=2), and RA-superior vena cava junction (n=2). ATs arose from the focal origins (11 ATs inside or at the border of low-voltage zone), with preferential conduction, breakout, and spread to the whole atrium. After applications of RF energy on the earliest activation site or the proximal portion of preferential conduction from AT origin, 13 ATs were eliminated without complication. During the follow-up period (8+/-5 months), 11 (91.7%) of the 12 patients with successful ablation were free of focal ATs.Focal AT originates from a small area and spreads out to the whole atrium through a preferential conduction. Application of RF energy guided by noncontact mapping system was effective and safe in eliminating focal AT.
Endothelin receptor antagonism in patients with chronic heart failure
Authors: M Love
Journal: Cardiovascular Research (2000)

Objective: The relative importance of ETA and ETB receptors in mediating the constrictor effects of endogenous endothelin-1 in patients with chronic heart failure is not known. The primary purpose of this study was to compare the acute effects of selective ETA and ETB receptor antagonists in vivo in healthy subjects and patients with chronic heart failure. Our secondary aim was to examine more closely the effect of chronic heart failure on endothelin biosynthesis. Methods: We studied the effects of BQ-123 (a selective ETA antagonist) and BQ-788 (a selective ETB antagonist) in ten healthy subjects and ten patients with chronic heart failure. Locally active doses of each antagonist were infused into the non-dominant brachial artery for 90 min on separate days at least 1 week apart. Changes in forearm blood flow were measured by venous occlusion plethysmography. Venous blood samples were obtained prior to antagonist infusion for assay of total endothelin, big endothelin-1 and C-terminal fragment immunoreactivity. Results: BQ-123 (100 nmol/min) increased blood flow by 54±10% (P<0.001) and 30±5% (P<0.001) in controls and heart failure patients, respectively. BQ-788 (1 nmol/min) reduced blood flow by 15±5% (P=0.036) and 9±4% (P=0.001) in controls and heart failure patients, respectively. Total endothelin immunoreactivity was non significantly greater in heart failure patients than controls (6.8±1.4 vs. 4.6±0.5 pM; P=0.13). Big endothelin-1 (2.6±0.4 vs. 1.7±0.1 pM; P=0.04) and C-terminal fragment immunoreactivity (2.1±0.3 vs. 0.6±0.1 pM; P<0.0001) were each significantly greater in heart failure patients than controls. Conclusions: Selective ETA receptor antagonism caused vasodilatation in the peripheral circulation of healthy subjects and patients with chronic heart failure while selective ETB receptor antagonism caused vasoconstriction in each group. ETB receptor antagonism may therefore cause potentially deleterious vasoconstriction in chronic heart failure. Chronic heart failure is associated with a significant increase in plasma big endothelin-1 and C-terminal fragment immunoreactivity.
Endothelial Cell Palmitoylproteomic Identifies Novel Lipid-Modified Targets and Potential Substrates for Protein Acyl Transferases
Authors: Ethan P. Marin, Behrad Derakhshan, TuKiet T. Lam, Alberto Davalos, William C. Sessa
Journal: Circulation Research (2012)

Rationale: Protein S-palmitoylation is the posttranslational attachment of a saturated 16-carbon palmitic acid to a cysteine side chain via a thioester bond. Palmitoylation can affect protein localization, trafficking, stability, and function. The extent and roles of palmitoylation in endothelial cell (EC) biology is not well-understood, partly because of technological limits on palmitoylprotein detection. Objective: To develop a method using acyl-biotinyl exchange technology coupled with mass spectrometry to globally isolate and identify palmitoylproteins in ECs. Methods and Results: More than 150 putative palmitoyl proteins were identified in ECs using acyl-biotinyl exchange and mass spectrometry. Among the novel palmitoylproteins identified is superoxide dismutase-1, an intensively studied enzyme that protects all cells from oxidative damage. Mutation of cysteine-6 prevents palmitoylation, leads to reduction in superoxide dismutase-1 activity in vivo and in vitro, and inhibits nuclear localization, thereby supporting a functional role for superoxide dismutase-1 palmitoylation. Moreover, we used acyl-biotinyl exchange to search for substrates of particular protein acyl transferases in ECs. We found that palmitoylation of the cell adhesion protein platelet endothelial cell adhesion molecule-1 is dependent on the protein acyl transferase ZDHHC21. We show that knockdown of ZDHHC21 leads to reduced levels of platelet endothelial cell adhesion molecule-1 at the cell surface. Conclusions: Our data demonstrate the utility of EC palmitoylproteomics to reveal new insights into the role of this important posttranslational lipid modification in EC biology.
Baseline neutrophil–lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use
Authors: D. Lorente, J. Mateo, A.J. Templeton, Z. Zafeiriou, D. Bianchini, R. Ferraldeschi, A. Bahl, L. Shen, Z. Su, O. Sartor, J.S. de Bono
Journal: Annals of Oncology (2014)
A Macrophage-Specific Fluorescent Probe for Intraoperative Lymph Node Staging
Authors: Jung Sun Yoo, Sung-Chan Lee, Zhi Yen Jow, Pamela Yun Xiang Koh, Young-Tae Chang
Journal: Cancer Research (2013)

Abstract Successful identification of nodal metastases in patients with cancer is crucial to prescribe suitable treatment regimens that can improve recurrence-free survival. Although some new imaging technologies for nodal staging have been developed, such as nanoparticle-enhanced MRI and quantum-dot–based fluorescence imaging, sound technologies for intraoperative differentiation of metastatic and inflamed lymph nodes remain lacking. In this study, we illustrate the feasibility of using a macrophage-specific fluorescent probe (MFP) to visualize sentinel lymph nodes during surgery, highlighting abnormalities related to inflammation and tumor infiltration with signal enhancement and reduction methods using this technology. MFP was identified by high-throughput screening of fluorescent small-molecule libraries synthesized with a diversity-oriented approach. It selectively visualized monocyte and macrophage cell populations in vitro, by live-cell imaging and flow cytometry, as well as in vivo, for imaging-guided surgery. Collectively, this study provides preclinical proof of concept for an intraoperative imaging platform to accurately assess lymph node status, eliminating the need for invasive nodal dissections that can contribute to complications of cancer therapy. Cancer Res; 74(1); 44–55. ©2013 AACR.