tbuckley/cabot-search huggingface dataset:
Vitronectin–αvβ3 Integrin Engagement Directs Hypoxia-Resistant mTOR Activity and Sustained Protein Synthesis Linked to Invasion by Breast Cancer Cells
Authors: Carolina Pola, Silvia C. Formenti, Robert J. Schneider
Journal: Cancer Research (2013)

Abstract The tumor microenvironment is a crucial player in the ability of cancer cells to acquire the ability to survive under the hypoxic environment and promote migration and invasion. Translational regulation is an essential part of cancer development and progression. Protein synthesis consumes considerable cellular metabolic energy and is therefore highly regulated, in turn controlling tumor cell proliferation and survival in extreme tumor–host conditions. Protein synthesis is typically downregulated by hypoxia, impairing cell proliferation and migration. Here, we show that breast cancer cells expressing integrin αvβ3, when engaging the extracellular matrix (ECM) protein vitronectin, strongly upregulate both mTOR activity and cap-dependent mRNA translation, which overrides their inhibition by hypoxia and facilitates tumor cell invasion. Interaction of vitronectin with integrin αvβ3 results in the continued activation of the kinase mTOR despite hypoxia through a mechanism that is dependent on integrin-linked kinase but is independent of focal adhesion kinase. Continuous activation of mTOR despite hypoxia involves release of translation initiation factor eIF4E from its repressor protein 4E-BP1, which is required for vitronectin-mediated tumor cell invasion. As integrin αvβ3 is associated with breast cancer cell invasion and metastasis to bone, we propose that the interaction with specific ECM proteins can influence cancer cell invasion, in part, by hyperactivation of mTOR, thereby promoting and sustaining protein synthesis under hypoxic conditions. Cancer Res; 73(14); 4571–8. ©2013 AACR.
Chromosomal reinsertion of broken RSS ends during T cell development
Authors: John D. Curry, Danae Schulz, Cynthia J. Guidos, Jayne S. Danska, Lauryl Nutter, Andre Nussenzweig, Mark S. Schlissel
Journal: The Journal of Experimental Medicine (2007)

The V(D)J recombinase catalyzes DNA transposition and translocation both in vitro and in vivo. Because lymphoid malignancies contain chromosomal translocations involving antigen receptor and protooncogene loci, it is critical to understand the types of "mistakes" made by the recombinase. Using a newly devised assay, we characterized 48 unique TCRbeta recombination signal sequence (RSS) end insertions in murine thymocyte and splenocyte genomic DNA samples. Nearly half of these events targeted "cryptic" RSS-like elements. In no instance did we detect target-site duplications, which is a hallmark of recombinase-mediated transposition in vitro. Rather, these insertions were most likely caused by either V(D)J recombination between a bona fide RSS and a cryptic RSS or the insertion of signal circles into chromosomal loci via a V(D)J recombination-like mechanism. Although wild-type, p53, p53 x scid, H2Ax, and ATM mutant thymocytes all showed similar levels of RSS end insertions, core-RAG2 mutant thymocytes showed a sevenfold greater frequency of such events. Thus, the noncore domain of RAG2 serves to limit the extent to which the integrity of the genome is threatened by mistargeting of V(D)J recombination.
Prognostic Factors for Survival in Adult Patients With Cerebral Low-Grade Glioma
Authors: Francesco Pignatti, Martin van den Bent, Desmond Curran, Channa Debruyne, Richard Sylvester, Patrick Therasse, Denes Áfra, Philippe Cornu, Michel Bolla, Charles Vecht, Abul B.M.F. Karim
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To identify prognostic factors for survival in adult patients with cerebral low-grade glioma (LGG), to derive a prognostic scoring system, and to validate results using an independent data set. PATIENTS AND METHODS: European Organization for Research and Treatment of Cancer (EORTC) trial 22844 and EORTC trial 22845 are the largest phase III trials ever carried out in adult patients with LGG. The trials were designed to investigate the dosage and timing of postoperative radiotherapy in LGG. Cox analysis was performed on 322 patients from EORTC trial 22844 (construction set), and the results were validated on 288 patients from trial 22845 (validation set). Patients with pilocytic astrocytomas were excluded from this prognostic factor analysis. RESULTS: Multivariate analysis on the construction set showed that age ≥ 40 years, astrocytoma histology subtype, largest diameter of the tumor ≥ 6 cm, tumor crossing the midline, and presence of neurologic deficit before surgery were unfavorable prognostic factors for survival. The total number of unfavorable factors present can be used to determine the prognostic score. Presence of up to two of these factors identifies the low-risk group, whereas a higher score identifies high-risk patients. The validity of the multivariate model and of the scoring system was confirmed in the validation set. CONCLUSION: In adult patients with LGG, older age, astrocytoma histology, presence of neurologic deficits before surgery, largest tumor diameter, and tumor crossing the midline were important prognostic factors for survival. These factors can be used to identify low-risk and high-risk patients.
Baseline nail disease in patients with moderate to severe psoriasis and response to treatment with infliximab during 1 year
Authors: Phoebe Rich, Christopher E.M. Griffiths, Kristian Reich, Frank O. Nestle, Richard K. Scher, Shu Li, Stephen Xu, Ming-Chun Hsu, Cynthia Guzzo
Journal: Journal of the American Academy of Dermatology (2007)
A Molecular Basis for the Exquisite CD1d-Restricted Antigen Specificity and Functional Responses of Natural Killer T Cells
Authors: Kwok S. Wun, Garth Cameron, Onisha Patel, Siew Siew Pang, Daniel G. Pellicci, Lucy C. Sullivan, Santosh Keshipeddy, Mary H. Young, Adam P. Uldrich, Meena S. Thakur, Stewart K. Richardson, Amy R. Howell, Petr A. Illarionov, Andrew G. Brooks, Gurdyal S. Besra, James McCluskey, Laurent Gapin, Steven A. Porcelli, Dale I. Godfrey, Jamie Rossjohn
Journal: Immunity (2011)
Pediatric <i>KIT</i>–Wild-Type and Platelet-Derived Growth Factor Receptor α–Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors
Authors: Katherine A. Janeway, Bernadette Liegl, Amy Harlow, Claudia Le, Antonio Perez-Atayde, Harry Kozakewich, Christopher L. Corless, Michael C. Heinrich, Jonathan A. Fletcher
Journal: Cancer Research (2007)

Abstract Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor α (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT–wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT–wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT–wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT–wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT–wild-type GIST. [Cancer Res 2007;67(19):9084–8]
ISsaga is an ensemble of web-based methods for high throughput identification and semi-automatic annotation of insertion sequences in prokaryotic genomes
Authors: Alessandro M Varani, Patricia Siguier, Edith Gourbeyre, Vincent Charneau, Mick Chandler
Journal: Genome biology (2011)

Abstract Insertion sequences (ISs) play a key role in prokaryotic genome evolution but are seldom well annotated. We describe a web application pipeline, ISsaga ( http://issaga.biotoul.fr/ISsaga/issaga_index.php ), that provides computational tools and methods for high-quality IS annotation. It uses established ISfinder annotation standards and permits rapid processing of single or multiple prokaryote genomes. ISsaga provides general prediction and annotation tools, information on genome context of individual ISs and a graphical overview of IS distribution around the genome of interest.
Relationship between cardioscopic images and histological changes in the left ventricle of patients with idiopathic myocarditis
Authors: Yasumi Uchida, Yasuto Uchida, Takeshi Sakurai, Masahito Kanai, Seiichiro Shirai, Osamu Nakagawa, Nobuyuki Hiruta
Journal: European Journal of Heart Failure (2011)

Endomyocardial biopsy is essential for definite diagnosis of idiopathic myocarditis. However, since endomyocardial biopsy is guided by fluoroscopy, whether or not the diseased myocardium is biopsied depends on chance, and this may lead to misdiagnosis. If the endocardial surface represents changes indicative of stages of myocarditis, staging of myocarditis and targeted cardioscope-guided biopsy could be used for accurate histological diagnosis.The relationship between left ventricular endocardial surface colour observed by cardioscopy and biopsy findings were examined in 78 patients with suspected idiopathic myocarditis. Of these, 59 patients were diagnosed histologically as idiopathic myocarditis. Endocardial colour was classified into red, milky white, purple, yellowish brown, or white. Biopsied specimens with red and milky white wall segments exhibited histological changes compatible with acute myocarditis; purple segments, active chronic myocarditis; and yellowish brown and white segments, inactive chronic myocarditis. The sensitivity, specificity, and predictive value of red and milky white colours for detecting acute myocarditis were 100, 100, and 100%, respectively; of purple for detecting active chronic myocarditis were 83, 92, and 78%, respectively; and yellowish brown and white for detecting inactive chronic myocarditis were 82, 74, and 53, respectively.Red and milky white endocardial surface colours predicted histological acute myocarditis, and purple predicted active chronic myocarditis. However, yellowish brown and white colours did not predict inactive chronic myocarditis.
Carvedilol, a new antioxidative β-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-κB activity
Authors: S Yang
Journal: Cardiovascular Research (2003)

Objective: The activation of T lymphocytes contributes to the inflammatory process of atherosclerosis. Here we examined the effects of carvedilol, a new β-blocker containing an antioxidative property, on the activation of T cells. Methods: Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA. The NF-κB and related protein activity was determined by electrophoretic mobility shift assays, Western blotting, kinase assays and transfection assays. Results: Carvedilol was nontoxic at concentrations ≦10 μM, however, higher dosages (≥20 μM) induced T cell apoptosis. We demonstrated that carvedilol inhibited cytokine production from various stimuli-activated T cells. Carvedilol also suppressed the expression of T cell activation markers, including CD25, CD69 and CD71. Molecular investigation indicated that carvedilol specifically downregulated NF-κB but not activator protein 1 DNA-binding activity in activated T cells. The inhibitory effect was likely due to its antioxidative property. Meanwhile, carvedilol prevented stimuli-induced IκBα degradation. Such an effect was mediated through the inhibition of IκBα kinase activity. The inhibitory specificity on NF-κB by carvedilol was also demonstrated in transfection assays. Conclusions: Our results demonstrated a novel therapeutic mechanism of carvedilol in atherosclerosis, namely the inhibition of T cell activation via downregulating NF-κB activity.
Long-Term Ovarian Cancer Survival Associated With Mutation in BRCA1 or BRCA2
Authors: John R. McLaughlin, Barry Rosen, Joel Moody, Tuya Pal, Isabel Fan, Patricia A. Shaw, Harvey A. Risch, Thomas A. Sellers, Ping Sun, Steven A. Narod
Journal: JNCI Journal of the National Cancer Institute (2012)

Studies have suggested that the 5-year survival of women with ovarian cancer and a BRCA1 or BRCA2 mutation is better than expected. We sought to evaluate the impact of carrying a BRCA1 or BRCA2 mutation on long-term survival of women after a diagnosis of invasive ovarian cancer.
Molecular functions of metallothionein and its role in hematological malignancies
Authors: Shinichiro Takahashi
Journal: Journal of Hematology & Oncology (2012)

Metallothionein (MT) was reported to be a potential negative regulator of apoptosis, and various reports have suggested that it may play roles in carcinogenesis and drug resistance, in at least a portion of cancer cells. The author summarizes the current understanding of the molecular functions of MT for tumor cell growth and drug resistance. These activities are regulated through intracellular metal ion modulation and free radical scavenging. Compared with analyses of solid tumors, few studies have analyzed the roles of MT in hematological malignancies. This review mainly describes the functions of MT in hematopoietic cells. Furthermore, through expression analyses of leukemias and lymphomas, the roles of MT in the biology of these diseases are particularly focused upon.
Ureteric Bud Apoptosis and Renal Hypoplasia in Transgenic PAX2-Bax Fetal Mice Mimics the Renal-Coloboma Syndrome
Authors: Alison Dziarmaga, Patsy Clark, Cherie Stayner, Jean Pierre Julien, Elena Torban, Paul Goodyer, Michael Eccles
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. In humans, PAX2 haploinsufficiency causes renal-coloboma syndrome (RCS) involving eye abnormalities, renal hypoplasia, and renal failure in early life. The authors previously showed that heterozygous mutant Pax2 mice have smaller kidneys with fewer nephrons, associated with elevated apoptosis in the ureteric bud (UB). However, PAX2 may have a variety of developmental functions such as effects on cell fate and differentiation. To determine whether apoptosis alone is sufficient to cause a UB branching deficit, the authors targeted a pro-apoptotic gene ( Bax α) to the embryonic kidney under the control of human PAX2 regulatory elements. The exogenous PAX2 promoter directed Bax α gene expression specifically to the developing kidney UB, eye, and mid/hindbrain. At E15.5 PAX2Promoter-Bax α fetal mice exhibited renal hypoplasia, elevated UB apoptosis, and retinal defects, mimicking the phenotype observed in RCS. The kidneys of E15.5 PAX2Promoter - Bax α fetal mice were 55% smaller than those of wild-type fetal mice, and they contained 70% of the normal level of UB branching. The data indicate that loss of Pax2 anti-apoptotic activity is sufficient to account for the reduced UB branching observed in RCS and suggest that elevated UB apoptosis may be a key process responsible for renal hypoplasia. The authors propose a morphogenic unit model in which cell survival influences the rate of UB branching and determines final nephron endowment. E-mail: meccles@otago.ac.nz
Novel Vascular Molecule Involved in Monocyte Adhesion to Aortic Endothelium in Models of Atherogenesis
Authors: Leslie M. McEvoy, Hailing Sun, Philip S. Tsao, John P. Cooke, Judith A. Berliner, Eugene C. Butcher
Journal: The Journal of Experimental Medicine (1997)

Adhesion of monocytes to the endothelium in lesion-prone areas is one of the earliest events in fatty streak formation leading to atherogenesis. The molecular basis of increased monocyte adhesion is not fully characterized. We have identified a novel vascular monocyte adhesion-associated protein, VMAP-1, that plays a role in adhesion of monocytes to activated endothelium. Originally selected for its ability to block binding of a mouse monocyte-like cell line (WEHI78/24) to cytokine- or LPS-stimulated cultured mouse endothelial cells in vitro, antiVMAP-1 mAb LM151 cross-reacts with rabbit endothelium and blocks binding of human monocytes to cultured rabbit aortic endothelial cells stimulated with minimally modified low density lipoprotein, thought to be a physiologically relevant atherogenic stimulus. Most importantly, LM151 prevents adhesion of normal monocytes and monocytoid cells to intact aortic endothelium from cholesterol-fed rabbits in an ex vivo assay. VMAP-1 is a 50-kD protein. Immunohistology of vessels reveals focal constitutive expression in aorta and other large vessels. VMAP-1 is thus a novel vascular adhesion-associated protein that appears to play a critical role in monocyte adhesion to aortic endothelial cells in atherogenesis in vivo.
Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells.
Authors: P D Greenberg, D E Kern, M A Cheever
Journal: The Journal of Experimental Medicine (1985)

The ability of noncytolytic Lyt-1+,2- T cells immune to FBL-3 leukemia to effect eradication of disseminated FBL-3 was studied. Adult thymectomized, irradiated, and T-depleted bone marrow-reconstituted (ATXBM) B6 hosts were cured of disseminated FBL-3 by treatment with 180 mg/kg cyclophosphamide (CY) and adoptively transferred Lyt-1+,2- T cells obtained from congenic B6/Thy-1.1 donors immune to FBL-3. Analysis of the T cell compartment of ATXBM hosts treated and rendered tumor-free by this therapy revealed that the only T cells present in the mice were donor-derived Lyt-1+,2- T cells. In vitro stimulation of these T cells with FBL-3 tumor cells, which express class I but no class II major histocompatibility complex antigens, induced lymphokine secretion, but did not result in the generation of cytotoxic T lymphocytes (CTL). Thus, in a setting in which mice lack Lyt-2+ T cells, and in which no CTL of either host or donor origin could be detected, immune Lyt-1+,2- T cells, in conjunction with CY, mediated eradication of a disseminated leukemia. The results suggest that delayed-type hypersensitivity responses induced by immune T cells represent a potentially useful effector mechanism for in vivo elimination of disseminated tumor cells.
Air Pollution and Cardiovascular Disease
Authors: Robert D. Brook, Barry Franklin, Wayne Cascio, Yuling Hong, George Howard, Michael Lipsett, Russell Luepker, Murray Mittleman, Jonathan Samet, Sidney C. Smith, Ira Tager
Journal: Circulation (2004)

Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.
Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx®) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group
Authors: H. Gogas, C. Papadimitriou, H.P. Kalofonos, D. Bafaloukos, G. Fountzilas, D. Tsavdaridis, A. Anagnostopoulos, A. Onyenadum, P. Papakostas, T. Economopoulos, C. Christodoulou, P. Kosmidis, C. Markopoulos
Journal: Annals of Oncology (2002)
Nasal eupnoeic inhalation of cold, dry air increases airway resistance in asthmatic patients
Authors: P Fontanari, MC Zattara-Hartmann, H Burnet, Y Jammes
Journal: European Respiratory Journal (1997)

The aim of this study was to establish a relationship between bronchial hyperreactivity to carbachol and reflex bronchomotor response to the activation of cold receptors in the nose, and also to examine whether any differences exist between asthmatic patients with or without symptoms of rhinitis. The changes in interrupting resistance (Rint) induced by nasal eupnoeic inhalation of cold (-5 degrees C) dry air were measured in 22 normal subjects and in 18 asthmatic patients (nine of whom had asthma with rhinitis and nine without) with bronchial hyperreactivity to carbachol. In normal individuals, nasal cold air challenge induced a significant increase in Rint (+31%). This was also the case in asthmatic patients (asthma with rhinitis +49%; asthma alone +40%), but the increase was not significantly larger than for normal individuals. The magnitude of Rint increase induced by nasal cold air breathing was correlated with the sensitivity to carbachol (defined as the dose inducing a 50% increase in specific airway conductance (D50)) in asthmatic patients with symptoms of rhinitis. These observations suggest that airway hyperreactivity is associated with enhanced bronchoconstrictor response to the activation of nasal cold receptors, particularly when rhinitis is present.
Hepatic manifestations of familial patent ductus venosus in adults
Authors: S Jacob, G Farr, D De Vun, H Takiff, A Mason
Journal: Gut (1999)

BACKGROUND The ductus venosus connects the umbilical vein to the inferior vena cava during fetal life and subsequently closes rapidly after birth. It is known as patent ductus venosus when it remains patent in adulthood. PATIENTS A 43 year old man with a history of panhypopituitarism presented with recurrent bouts of pedal oedema associated with fatigue, hypoalbuminaemia, and elevated prothrombin time. An ultrasound examination of his abdomen with Doppler revealed notable attenuation of the main portal vein with diminished intrahepatic branches; a computed tomography scan with angiography revealed a large collateral vein within the liver consistent with a patent ductus venosus. Sequential liver biopsies showed a considerable reduction in the calibre and number of the portal veins. His younger brother, who was diagnosed with alcohol related cirrhosis, suffered from intermittent bouts of encephalopathy and was found to have the same vascular lesion. A third brother was found to have a patent ductus venosus as well as two large hepatic masses consistent with focal nodular hyperplasia. CONCLUSION The syndrome of familial patent ductus venosus has only previously been described in three infant brothers who presented with hepatic encephalopathy and fatty degeneration of the liver. This report documents three brothers with a patent ductus venosus presenting in adulthood with different manifestations of liver disease. The presence of the same vascular anomaly in three brothers is highly suggestive of a recessive genetic trait with an anatomical manifestation of patent ductus venosus.