tbuckley/cabot-search huggingface dataset:
The RET signaling pathway: Linking developmental and neoplastic roles
Authors: Lois M. Mulligan
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

SY27-1 

Although many of the genes now recognized as contributing to neoplastic transformation have similar and predictable roles in cell growth, migration and proliferation in most cell types, a number of genes have now been recognized as having normal primary roles specifically in organismal development. Mutations of these genes contribute to tumorigenesis in specific characteristic cell types, however, in some cases the type of mutation, and the developmental window in which it occurs, can determine whether the genetic variant contributes to neoplastic changes or to an abnormality of normal development. One gene with two such diverse effects is the RET proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase that is required for development of neural crest derivatives, the central and peripheral nervous systems and the kidney. Activating missense mutations of RET give rise to the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) which is characterized by medullary thyroid carcinoma, the adrenal tumour pheochromocytoma and by parathyroid hyperplasia. In each case, these mutations result in constitutive activation of the receptor. Intriguingly however, mutations that result in inactivation of the RET receptor, or significant reduction in cell surface associated RET protein, lead to a common congenital abnormality Hirschsprung disease (HSCR), characterized by absence of the parasympathetic ganglia of varying extents of the distal colon. Comparisons of the diametrically opposite effects of MEN 2 and HSCR RET-mutations have suggested that many tissues are highly sensitive to relatively small changes in the levels of RET, but that different tissues have unique sensitivity to increased or decreased RET activity. Recent studies that have provided some insight into normal RET signal transduction and the mechanisms by which RET mutations contribute to disease phenotype will be discussed.
Small molecule-mediated inhibition of Factor VIIa catalytic activity blocks fVIIa:TF cellular signaling and chemokine secretion in human tumor cell lines
Authors: Leslie J. Holsinger, Bill Shrader, Catherine Magill, Meire Bremer, Jennifer Kattler, Jim Janc, Peter Young, Wendy Young
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4708 

In addition to its role in coagulation, Factor VIIa (fVIIa) binding to TF has been demonstrated to activate a variety of intracellular signaling pathways including MAPK, AKT, and Src. This activity has been shown to require TF binding as well as fVIIa protease activity. TF overexpression in tumor epithelial cells and tumor vasculature has been linked to prognosis. However a precise role for fVIIa:TF signaling in tumor cell growth and survival has not yet been established. We have demonstrated that fVIIa is able to activate MAPK, AKT, and early-response gene induction in the BxPC3 pancreatic human tumor cell line at physiologic (0.1-10nM) concentrations. TF expression in the tumor cell line is required for this intracellular signaling. The chemically-inactivated form of fVIIa, fVIIai, is unable to activate these signaling pathways. In addition, preincubation of fVIIa with potent, fVIIa-selective, reversible small molecule inhibitors of fVIIa protease activity inhibited the activation of MAPK and early-response gene induction in a dose-dependent manner. These data demonstrate that fVIIa catalytic activity is required for its effect on intracellular signaling, and indicate that small molecule inhibitors of fVIIa:TF activity on tumor epithelial cells may have direct anti-tumor efficacy. fVIIa also induced the secretion of chemokines IL-8, GROα, and VEGF in the human breast tumor cell line MDA-MB-231. fVIIai was unable to induce chemokine secretion. fVIIa-specific small molecule inhibitors of fVIIa protease activity inhibited this secretion in the presence or absence of serum components. IL-8 is an autocrine growth factor in tumors that stimulates chemotaxis and invasion, and also exhibits effects on endothelial cell survival and proliferation and may directly effect the formation and maintenance of tumor vasculature. IL-8 secretion was not induced by fXa or a number of other serine proteases including urokinase, thrombin, and tryptase indicating that this activity is specific to the fVIIa protease. In summary, fVIIa mediated secretion of pro-angiogenic chemokines as well as signaling events which regulate tumor cell growth and survival. These fVIIa-specific effects were blocked with small molecule inhibitors of fVIIa protease activity. Thus, small molecule inhibitors of fVIIa may be expected to have utility as anti-tumor agents in the treatment of malignancies.
Low-dose enoximone improves exercise capacity in chronic heart failure∗∗A list of the Enoximone Study Group Members and institutional affiliations is provided in the appendix.
Authors: Brian D Lowes, Michael Higginbotham, Lawrence Petrovich, Marcus A DeWood, Mark A Greenberg, Peter S Rahko, G.William Dec, Thierry H LeJemtel, Robert L Roden, Margo M Schleman, Alastair D Robertson, Richard J Gorczynski, Michael R Bristow
Journal: Journal of the American College of Cardiology (2000)
Primer skatrisiyel alopesi: Histopatolojik bulgular klinik varyantların ayırt edilmesini sağlamamaktadır
Authors: Paradi Mirmirani, Andrea Willey, John T. Headington, Kurt Stenn, Timothy H. McCalmont veVera H. PriceSan Francisco, Ann Arbor, Michigan ve Philadelphia, Pennsylvania
Journal: Journal of the American Academy of Dermatology (2005)
Tumor necrosis factor- α in liver transplantation and resection
Authors: Olivier Chazouillères, Jérôme Guéchot, Pierre Balladur, Jean-Pierre Masini, Eric Delva, Abderrhamane Laribi, Jacqueline Giboudeau, André Lienhart, Rolland Parc, Raoul Poupon, Laurent Hannoun
Journal: Journal of Hepatology (1992)
886. Determination of Osteoprogenitor-Specific Promoter Activity in Murine Mesenchymal Stem Cells by Recombinant Adeno-Associated Virus Transduction
Authors: Hairong Peng, Arvydas Usas, Brian Gearhart, Johnny Huard
Journal: Molecular Therapy (2004)

Introduction: Bone formation and bone healing require concerted interactions among many different pathways, including osteogenesis and angiogenesis. Previous studies have shown that the angiogenic factor VEGF is important for both normal bone development and BMP4-induced bone formation. More importantly, VEGF can synergistically enhance the bone formation and bone healing elicited by BMP4. The aim of this study was to determine whether VEGF also can enhance the bone formation and bone healing elicited by BMP2, another widely studied BMP.
Abstract 3551: Cyclophilin a Promotes Angiotensin II-Induced Inflammation and Cardiovascular Hypertrophy in Mice
Authors: Kimio Satoh, Liam Casey, Michael R O’Dell, Patrizia Nigro, Amy Mohan, Yan Lu, Jeffrey Alexis, Chen Yan, Burns C Blaxall, Bradford C Berk
Journal: Circulation (2008)

Background - Cyclophilin A (CyPA) is a chaperone protein secreted from vascular smooth muscle cells (VSMC) in response to reactive oxygen species (ROS). We have recently demonstrated that extracellular CyPA stimulates at least 3 signaling pathways (ERK1/2, Akt and JAK) and mediates numerous cellular effects of ROS. Angiotensin II (Ang II) induces ROS through NADPH oxidases and activates matrix metalloproteinase (MMP) in VSMC. ROS and MMPs have been demonstrated to mediate cardiac hypertrophy and remodeling. We hypothesized that VSMC-derived CyPA contributes to AngII-induced cardiovascular hypertrophy in vivo due to its proinflammatory properties. Methods and Results - ApoE −/− and ApoE −/− CyPA −/− mice were treated with AngII (1000 ng/min/kg for 4 weeks) to induce cardiac hypertrophy. Long-term infusion of AngII significantly increased heart/body weight ratio in ApoE −/− mice, which was significantly less in ApoE −/− CyPA −/− mice (6.6±1.0 vs. 4.8±0.7, P &lt;0.01). Echocar-diography confirmed a significantly greater increase in LV mass in ApoE −/− mice compared to ApoE −/− CyPA −/− mice (112% vs. 47%). Perivascular accumulation of inflammatory cells and cardiac myofibroblasts in ApoE −/− mice was significantly greater than in ApoE −/− CyPA −/− mice. Consequently, coronary artery ROS production (DHE fluorescence) and MMP activation (in situ zymography) were markedly increased by AngII in ApoE −/− mice compared to ApoE −/− CyPA −/− mice. To determine the source of CyPA, bone marrow cells (BMCs) transplantation was performed. The heart/body weight ratio was still higher in ApoE −/− mice compared with ApoE −/− CyPA −/− mice after reconstitution with GFP + CyPA +/+ BMCs (6.7±0.6 vs. 5.6±0.9, P &lt;0.01). Recruitment of GFP + BMCs to the heart in chimeric ApoE −/− mice was significantly greater than the chimeric ApoE −/− CyPA −/− mice (count/area; 218±63 vs. 109±43, P &lt;0.01). To prove a vascular source of CyPA was essential, VSMC-specific CyPA overexpressing mice were generated. In these mice there was a significant increase in cardiac MMP activity after AngII infusion (VSMC-Tg &gt; WT &gt; CyPA −/− ). Conclusion - CyPA is a novel mediator of AngII-induced cardiac hypertrophy by stimulating vascular ROS production, MMP activation, and inflammatory cell recruitment. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
Abstract 17517: Genetics of Left Ventricular Noncompaction Cardiomyopathy
Authors: Jan Haas, Zhu Feng, Christian Geier, Regina Pribe-Wolferts, Karen S Frese, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Barbara Peil, Justo Lorenzo Bermejo, Jennifer Franke, Andreas Keller, Yuhua Liao, Hugo A Katus, Benjamin Meder
Journal: Circulation (2014)

Left ventricular noncompaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmias, thrombembolic events, and sudden cardiac death. To better understand the contribution of genetic factors to this disease, allowing a better diagnosis, counseling of affected families and estimation of prognosis, we have performed whole-exome deep-sequencing on a cohort of in 104 subjects (67 unrelated LVNC probands, 26 affected relatives form 15 families and 11 additional healthy relatives). By annotating the detected variants with mutation databases (HGMD), we were able to for the first time show an overlap between the distinct causes of LVNC and other genetic cardiomyopathies, as 8 mutations were previously reported to cause hypertrophic cardiomyopathy (HCM), 9 dilated cardiomyopathy (DCM) and 6 arrhythmogenic right ventricular cardiomyopathy (ARVC). Besides already known genetic causes, we identified a number of genes contributing to different pathways, so far not discussed to be of relevance for LVNC. From those, TTN truncating mutations were very frequent, affecting 17.9% of all index patients and one fifth of the familial cases. For two genes, which have already been linked to cardiac noncompaction in animal models, we are first to describe a relevant number of patients carrying mutations in these genes NCOR2 (frequency = 7.5%) and XIRP2 (4.5%). By performing segregation and linkage analyses, as well as in vivo studies, we provide for the first time evidence for a gene that was previously not known to cause a human disease, Compactin1. In conclusion, we show that LVNC has a substantial genetic component and suggest new candidate genes for a functional dissection of their contribution to cardiac development and as potential therapeutic target.
A CASE OF PERSISTENT LYMPHEDEMA INVOLVING THE LEFT ARM, LEFT FACE, AND LEFT THORAX
Authors: Ramsdell Gurney, Franklyn Huber
Journal: Annals of Internal Medicine (1934)

Article1 May 1934A CASE OF PERSISTENT LYMPHEDEMA INVOLVING THE LEFT ARM, LEFT FACE, AND LEFT THORAXRAMSDELL GURNEY, M.D., FRANKLYN HUBER, M.D.RAMSDELL GURNEY, M.D.Search for more papers by this author, FRANKLYN HUBER, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-7-11-1431 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThis case is presented because of the paucity of reports on persistent lymphedema in the locations present in this patient.CASE REPORTOn May 17, 1933, a white, unmarried, 16 year old American girl came to the Out-Patient Department of the Buffalo General Hospital for treatment of persistent, painless swelling of the left arm and left side of the face. According to the girl's mother, the child was taken to a doctor at the age of six weeks for an infection in her left eye. At that time the doctor called attention to the enlargement of the left arm and...References1. MILROY WF: An undescribed variety of hereditary edema, New York Med. Jr., 1892, lvi, 505-508. Google Scholar2. HOPEFRENCH WBH: Persistent hereditary edema of the legs with acute exacerbations: Milroy's disease, Quart. Jr. Med., 1907-08, i, 312-330. Google Scholar3. SLATMANN AF: Ein Fall von Trophoedema chronicum faciei in seinen Beziehungen zu der Menstruation, Zentralbl. f. Gynäk., 1927, li, 2279-2282. Google Scholar4. REICHERT FL: Recognition of elephantiasis and of elephantoid conditions by soft tissue roentgenograms, with report of experimental lymphedema, Arch. Surg., 1930, xx, 543-568. CrossrefGoogle Scholar5. PIERSOL GM: Human anatomy, 6th ed., 1918, J. B. Lippincott, Philadelphia, p. 944. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Buffalo, New York*Received for publication March 2, 1934.From The Service of Clayton W. Greene, M.D., Buffalo General Hospital, and the School of Medicine, University of Buffalo. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1934Volume 7, Issue 11Page: 1431-1435KeywordsHospital medicineInflammationLymphedemaOutpatientsPediatric infectionsThorax Issue Published: 1 May 1934 PDF DownloadLoading ...
Biological Bases and Clinical Implications of Tumor Radioresistance
Authors: G.H. Fletcher, C. Nerri, R. Withers
Journal: JNCI Journal of the National Cancer Institute (1980)

International experts discuss the relevance of biology and radiation therapy, offer critical evaluations of therapeutic procedures and make recommendations for future development of methods of cancer treatment. Topics include the limitations of normal tissue tolerance, attempts to improve the therapeutic ratio by manipulation of the time factor, and a review of the present state-of-the-art giving the results of conventional irradiation and describing some of the ways of maximizing the effectiveness of existing means of treatment.
Dementia and Testosterone Levels in Men
Authors: Richard L Bowen, Ralph N Martins, Christopher W Gregory, Mark A Smith, Craig S Atwood
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: A randomized trial (Annals of Internal Medicine (2008) 149, (521-530))
Authors: G. Simonneau, L. J. Rubin, N. Galié, R. J. Barst, T. R. Fleming, A. E. Frost
Journal: Annals of Internal Medicine (2009)
224. Adenoviral Co-Delivery of BDNF and Noggin Induces Striatal Neuronal Replacement and Delays Motor Impairment in a Transgenic Model of Huntington's Disease
Authors: Sung-Rae Cho, Eva Chmielnicki, Steven A. Goldman
Journal: Molecular Therapy (2004)

Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates the addition of new medium spiny neurons to the adult neostriatum, from endogenous subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis, potentiates BDNF-induced neuronal recruitment. We asked if these agents might be used to stimulate striatal neurogenesis in R6/2 mice, a transgenic model of Huntington's Disease engineered to express a roughly 145 CAG repeat expansion in the first exon of the huntingtin gene. R6/2 or wild-type mice (n = 18 each) were given intraventricular injections of either AdBDNF/AdNoggin, AdBDNF, AdNull or saline, all at 6 weeks of age. All were then injected daily for 30 days with BrdU to tag new cells, the neurons among which were identified by labeling for βIII-tubulin, NeuN, GAD67 or DARPP-32. AdBDNF/AdNoggin-treated R6/2 mice showed substantial striatal neurogenesis (277.0 ± 52.7 BrdU+/βIII-tubulin+ neurons/mm3), significantly so compared to AdBDNF- (135.0 ± 34.1), AdNull- (20.1 ± 6.5) and saline- (5.1 ± 7.8) treated R6/2 mice (p<0.01 by ANOVA). Moreover, the number of new neurons in the AdBDNF/AdNoggin-treated R6/2 striatum did not differ significantly from that of AdBDNF/AdNoggin-treated wild-type controls (219.9 ± 19.4/mm3), indicating that R6/2 mice were as able as wild-types to mount a neurogenic response to treatment. Saline and AdNull-treated R6/2 mice, but not their wild-type controls, also exhibited striatal neuronal addition, indicating a degree of compensatory neurogenesis in R6/2 mice. The new neurons were recruited largely as DARPP-32+/GAD67+ GABAergic medium spiny cells, and Fluorogold injections confirmed that they extended fibers to the globus pallidus. Rotarod testing revealed that AdBDNF/AdNoggin-treated R6/2 mice exhibited both a delayed and decelerated progression of motor impairment, relative to AdNull-injected R6/2 mice. Thus, ependymal overexpression of BDNF and noggin induced the recruitment of substantial numbers of new GABAergic medium spiny projection neurons to the R6/2 huntingtin transgenic neostriatum, and this was associated with a slower onset of motor impairment in affected animals. These data suggest the feasibility of directed neuronal regeneration as a therapeutic option in Huntington's disease.
Misdiagnosis and delay in referral of children with localized scleroderma
Authors: L. Weibel, B. Laguda, D. Atherton, J.I. Harper
Journal: British Journal of Dermatology (2011)

Localized scleroderma (LS) usually begins in childhood with a broad clinical spectrum and the diagnosis is often delayed.To investigate the diagnostic pathway in a large cohort of paediatric patients with LS, to identify the duration until correct diagnosis and to characterize clinical clues for early diagnosis.A retrospective case note review of 50 children with LS.The median (range) age at disease onset was 5·2 (0·1-14·4) years and disease duration until diagnosis 11·1 (1·8-79) months. The patients were first seen by a general practitioner (or paediatrician) after 1·2 (0·2-48·7) months and in none of the cases was the condition recognized at presentation according to a parental questionnaire (no diagnosis in 44%, misdiagnosis of atopic eczema 20%, melanocytic naevus 8%, fungal infection 6%, bruise 4%, varicose vein 4%, bacterial infection 4% and others). The patients were referred to a local specialist (dermatologist in 72%) after a disease duration of 7·5 (1·0-70·9) months and in 64% the correct diagnosis was established. In 20% the diagnosis remained unknown, 8% were misdiagnosed as port-wine stains and others as atopic eczema and melanocytic naevus. The correct diagnosis was eventually identified by the referring dermatologists, the paediatric dermatologists at our hospital, external maxillofacial surgeons and a paediatrician in 29 (58%), 17 (34%), 3 (6%) and 1 (2%), respectively. Histology was performed in 15 (30%). The patients were commenced on appropriate treatment after a disease duration of 16·6 (1·8-113·4) months. The main clinical diagnostic clues were: Blaschko-linear distribution 76%, atrophic changes 68%, skin fibrosis 40% and loss of scalp hair or eyelashes 36%.Physicians involved in the care of these children need to be aware of the characteristic clinical appearance of LS for early recognition and prompt initiation of treatment.
Abstract 15898: Toll-Like Receptor 2 Methylation and Dietary Flavonoid Intake Modify the Association Between Fine Particle Exposure and Cardiac Autonomic Dysfunction: The Normative Aging Study
Authors: Jia Zhong, Elena Colicino, Xinyi Lin, Amar Mehta, Itai Kloog, Antonella Zanobetti, Hyang-Min Byun, Marie-Abèle Bind, Laura Cantone, Diddier Prada, Letizia Tarantini, David Sparrow, Pantel Vokonas, Joel Schwartz, Andrea Baccarelli
Journal: Circulation (2014)

Introduction: Short-term exposure to fine particles (PM 2.5 ) is associated with reduced heart rate variability (HRV), a strong predictor of cardiac mortality among the elderly. Identifying modifiable factors that confer susceptibility is essential for personalized intervention. We evaluated whether Toll-Like Receptor 2 (TLR2) methylation [[Unable to Display Character: &amp;#8211;]] a reversible epigenetic process affecting immunoregulation [[Unable to Display Character: &amp;#8211;]] modified the effect of PM 2.5 on HRV, and investigated the impact of flavonoid and folic acid intake on TLR2 methylation. Methods: We collected longitudinal measures of HRV and PM 2.5 over 11 years among 573 elderly men from the Normative Aging Study. TLR2 methylation was analyzed using bisulfite-treated Pyrosequencing from 500 participants. Harvard Food Frequency Questionnaire was administrated to assess average daily flavonoid and folic acid intake in the past year. Results: Every 10 μg/m 3 increase in 48 hours PM 2.5 moving average was associated with 7.23% (95% CI, 2.95%, 11.33%; P = 0.03) and 13.88% (95% CI, 1.39%, 24.79%; P = 0.04) reduction in the standard deviation of normal-to-normal intervals (SDNN) and low frequency (LF), respectively. TLR2 hypermethylation exacerbated the post-exposure SDNN, LF, and high frequency (HF) reduction ( P global = 0.03, 0.05, 0.04, respectively). Every 10-fold increase in flavonoid intake was associated with 0.41 %5mC lower in TLR2 methylation (95% CI, 0.04, 0.78; P = 0.03). High flavonoid intake weakened the association between PM 2.5 and LF by lessening 33.01% (95% CI, 1.56, 74.22; P = 0.04) LF reduction per 10 μg/m 3 increase in PM 2.5 , compared to the low intake group. Folic acid intake was not associated with TLR2 methylation. Conclusion: TLR2 hypermethylation confers the vulnerability to post-exposure HRV decline of the elderly when confronted with air pollution peaks, while high flavonoid intake emolliates the hazardous effect of pollution, likely through regulating TLR2 methylation.