tbuckley/cabot-search huggingface dataset:
Cytosolic phospholipase A2 regulates Golgi structure and modulates intracellular trafficking of membrane proteins
Authors: Gabriel J. Choukroun, Vladimir Marshansky, Corinne E. Gustafson, Mary McKee, Roger J. Hajjar, Anthony Rosenzweig, Dennis Brown, Joseph V. Bonventre
Journal: Journal of Clinical Investigation (2000)

The Golgi complex and the trans-Golgi network are critical cellular organelles involved in the endocytic and biosynthetic pathways of protein trafficking. Lipids have been implicated in the regulation of membrane-protein trafficking, vesicular fusion, and targeting. We have explored the role of cytosolic group IV phospholipase A2 (cPLA2) in membrane-protein trafficking in kidney epithelial cells. Adenoviral expression of cPLA2 in LLC-PK1 kidney epithelial cells prevents constitutive trafficking to the plasma membrane of an aquaporin 2-green fluorescent protein chimera, with retention of the protein in the rough endoplasmic reticulum. Plasma membrane Na+-K+-ATPase α-subunit localization is markedly reduced in cells expressing cPLA2, whereas the trafficking of a Cl–/HCO3– anion exchanger to the plasma membrane is not altered in these cells. Expression of cPLA2 results in dispersion of giantin and β-COP from their normal, condensed Golgi localization, and in marked disruption of the Golgi cisternae. cPLA2 is present in Golgi fractions from noninfected LLC-PK1 cells and rat kidney cortex. The distribution of tubulin and actin was not altered by cPLA2, indicating that the microtubule and actin cytoskeleton remain intact. Total cellular protein synthesis is unaffected by the increase in cPLA2 activity. Thus cPLA2 plays an important role in determining Golgi architecture and selective control of constitutive membrane-protein trafficking in renal epithelial cells.
Sleeping Beauty Transposition: Biology and Applications for Molecular Therapy
Authors: Zsuzsanna Izsvák, Zoltán Ivics
Journal: Molecular Therapy (2004)

Transposable elements can be considered as natural, nonviral gene-delivery vehicles and are valuable and widely used tools for germ-line transgenesis and insertional mutagenesis in invertebrate systems such as flies and worms. Such tools were not available for genome manipulations in vertebrates until recently, when an active element was resurrected from transposon fossils found in fish genomes. This element, the Sleeping Beauty transposon, shows efficient transposition in cells of a wide range of vertebrates, including humans. Sleeping Beauty transposition is a cut-and-paste process, during which the element "jumps" from one DNA molecule to another. Transposon integration into chromosomes provides the basis for long-term, or possibly permanent, transgene expression in transgenic cells and organisms. Thus, the reconstruction of the Sleeping Beauty element generated considerable interest in developing efficient and safe vectors for vertebrate transgenesis as well as for human gene therapy. In this review we summarize our current knowledge of Sleeping Beauty biology and describe the strengths and current limitations of transposon technology for gene therapeutic applications.
Abstract P3-07-06: BRCA mutations among Hispanic breast cancer patients of Mexican origin in El Paso, TX
Authors: ZA Nahleh, R Heydarian, JS Saldivar, K Castaneda, L Sanchez
Journal: Cancer Research (2013)

Abstract Introduction: El Paso, TX is a large American-Mexican border city of population around 900,000, 85% Hispanic of Mexican origin. Limited cancer research has been conducted in this population. The relative homogeneity of this Hispanic population lends a unique opportunity to study the prevalence of BRCA mutations among Hispanic patients of Mexican origin, to identify reported Mexican founder or recurrent mutations, and to study the breast cancer characteristics in mutation carriers. Methods: Hispanic women with a personal history of breast cancer, who presented consecutively for genetic cancer risk assessment, were enrolled in an Institutional Review Board -approved registry and underwent BRCA testing bases on NCCN guidelines. The characteristics of tumors and patients with positive BRCA mutation were analyzed. Descriptive statistics were utilized. Results: 59 patients were screened; 13 patients (22%) tested positive. Mean age was 50 years; 8 patients (62%) had stages I or II, 2 patients stage III, and 3 unknown. 10 (77%) ductal, 1 (7%) lobular and 2 undetermined; 30% had ER positive tumors versus 61% ER negative; 69% had HER2 -neu negative tumors and 23% HER2-neu positive; 62% were triple negative. Nine patients (69%) were diagnosed with breast cancer at younger than 50 years. Median BMI was 31.78. Ten patients had BRCA1 mutations and 3 BRCA2 mutations. A total of 9 unique deleterious BRCA Mutations were observed, BRCA1 R71G (330A&amp;gt;G);del exons 1-2;C1787S(5478T&amp;gt;A) and G1788D(5482 G&amp;gt;A); C1225X (3794 C&amp;gt;A); A 1708E(5242 C&amp;gt;A); R1751X(5370C&amp;gt;T; and del exons 9-12 and BRCA2 Q742X (2452 C&amp;gt;T); and 3492 insT Conclusion: This study confirms that breast cancer patients with BRCA mutations in the El Paso, TX present at a younger age, and have predominantly triple negative tumors. Of particular interest is 44% (4 of 9) BRCA mutations (BRCA1 exon 9-12 del; C1787S &amp; G1788D and BRCA 2 3492insT; Q742X) identified have been reported as recurrent mutations in Hispanic individuals from Mexico as the country of origin, including BRCA1 ex9-12del, the 1st Mexican founder mutation and 100% of the BRCA2 mutations. A more cost-effective approach to initial screening of Hispanic individuals based on country of origin may be desirable and would potentially decrease the number of cases requiring complete sequencing. Increasing breast cancer awareness and encouraging genetic counseling among high risk younger patients of Mexican descent is also needed. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-06.
Meningeal Leukemia
Authors: Roland T. Skeel
Journal: JAMA (1968)

The syndrome of meningeal leukemia is one of the major complications of acute leukemia.<sup>1,2</sup>The manifestations of the clinical syndrome include headache, nausea, vomiting, eye signs, cranial nerve palsies, and lethargy, and may be associated with increased intracranial pressure. The observation that cerebrospinal fluid (CSF) pleocytosis is almost always associated with the clinical syndrome has shifted the emphasis in the criteria for diagnosis from dependence on clinical signs and symptoms to a greater reliance on laboratory findings.<sup>3,4</sup>More recent studies further demonstrate that the CSF pleocytosis may precede the symptoms. In the review of cases reported by Nies et al,<sup>3</sup>the diagnosis of meningeal leukemia was said to be established by the presence of ten or more mononuclear cells per cubic millimeter in the spinal fluid. Judged by this criterion, of 38 cases of meningeal leukemia, 14 had no presenting signs or symptoms at the time of
Vascular dysfunction in human and rat cirrhosis: Role of receptor-desensitizing and calcium-sensitizing proteins
Authors: Martin Hennenberg, Jonel Trebicka, Erwin Biecker, Michael Schepke, Tilman Sauerbruch, Jörg Heller
Journal: Hepatology (2007)

In cirrhosis, vascular hypocontractility leads to vasodilation and contributes to portal hypertension. Impaired activation of contractile pathways contributes to vascular hypocontractility. Angiotensin II type 1 receptors (AT1-Rs) are coupled to the contraction-mediating RhoA/Rho-kinase pathway and may be desensitized by phosphorylation through G-protein-coupled receptor kinases (GRKs) and binding of β-arrestin-2. In the present study, we analyzed vascular hypocontractility to angiotensin II in cirrhosis. Human hepatic arteries were obtained during liver transplantation. In rats, cirrhosis was induced by bile duct ligation (BDL). Contractility of rat aortic rings was measured myographically. Protein expression and phosphorylation were analyzed by Western blot analysis. Immunoprecipitation was performed with protein A–coupled Sepharose beads. Myosin light chain (MLC) phosphatase activity was assessed as dephosphorylation of MLCs. Aortas from BDL rats were hyporeactive to angiotensin II and extracellular Ca2+. Expression of AT1-R and Gαq/11,12,13 remained unchanged in hypocontractile rat and human vessels, whereas GRK-2 and β-arrestin-2 were up-regulated. The binding of β-arrestin-2 to the AT1-R was increased in hypocontractile rat and human vessels. Inhibition of angiotensin II–induced aortic contraction by the Rho-kinase inhibitor Y-27632 was pronounced in BDL rats. Basal phosphorylation of the ROK-2 substrate moesin was reduced in vessels from rats and patients with cirrhosis. Analysis of the expression and phosphorylation of Ca2+-sensitizing proteins (MYPT1 and CPI-17) in vessels from rats and patients with cirrhosis suggested decreased Ca2+ sensitivity. Angiotensin II–stimulated moesin phosphorylation was decreased in aortas from BDL rats. MLC phosphatase activity was elevated in aortas from BDL rats. Conclusion : Vascular hypocontractility to angiotensin II in cirrhosis does not result from changes in expression of AT1-Rs or G-proteins. Our data suggest that in cirrhosis-induced vasodilation, the AT1-R is desensitized by GRK-2 and β-arrestin-2 and that changed patterns of phosphorylated Ca2+-sensitizing proteins decrease Ca2+ sensitivity.
High Numbers of Tumor-Infiltrating Programmed Cell Death 1–Positive Regulatory Lymphocytes Are Associated With Improved Overall Survival in Follicular Lymphoma
Authors: Joaquim Carreras, Armando Lopez-Guillermo, Giovanna Roncador, Neus Villamor, Lluis Colomo, Antonio Martinez, Rifat Hamoudi, William J. Howat, Emili Montserrat, Elias Campo
Journal: Journal of Clinical Oncology (2009)

Tumor microenvironment influences the behavior of follicular lymphoma (FL), although the specific cell subsets involved are not well known. The aim of this study was to determine the impact of programmed cell death 1 (PD-1) -positive inhibitory immunoregulatory lymphoid cells in the clinicobiologic features and outcome of patients with FL.We examined samples from 100 patients (53 men and 47 women; median age, 54 years) at diagnosis, as well as in 32 patients at first relapse, with a recently generated monoclonal antibody against PD-1. The cells were quantified using computerized image analysis. Additional analysis consisted of double immunofluorescence and flow cytometry.PD-1 expression was alternative to FOXP3 in lymphoid cells from both reactive tonsils and FL. At diagnosis, the median percentage of PD-1-positive cells was 14% (range, 0.1% to 74%). Patients with grade 3 FL, poor performance status, and high serum lactate dehydrogenase showed lower numbers of PD-1-positive cells. After a median follow-up of 6.2 years, patients with PD-1-positive cells <or= 5% (n = 25), 6% to 33% (n = 50), and more than 33% (n = 25) had a 5-year progression-free survival rate of 20%, 46%, and 48% (P = .038) and overall survival (OS) of 50%, 77%, and 95% (P = .004), respectively. PD-1 and FL International Prognostic Index maintained prognostic value for OS in multivariate analysis. Patients with PD-1-positive cells <or= 5% showed a higher risk of histologic transformation. At that time, transformed diffuse large B-cell lymphomas had lower percentage of PD-1-positive cells than FL.A high content of PD-1-positive cells predicted favorable outcome of FL patients, whereas a marked reduction is observed in transformation.
Racism in medicine
Authors: H M C Corfield
Journal: Journal of the Royal Society of Medicine (2002)

In his editorial (October 2001 JRSM, pp. 499-500) Dr Sheikh did not mention one crucial question. To what extent is it a duty when making a public-service appointment to give the consumers what they want? Just as some women prefer a woman doctor so do some individuals prefer a black, brown or white one. This is not racism (or sexism) but personal choice. Social mores should never be confused with public prejudice, as priests and politicians now constantly remind us. The cultivation of guilt is quite unhelpful. Openness and humour are far better, even when it is no laughing matter.
Fibrosing alveolitis and treatment with sulphasalazine
Authors: D. Davies, A. MacFarlane
Journal: Gut (1974)

A woman with ulcerative colitis was treated with sulphasalazine and prednisolone. After four months9 treatment she began to get short of breath and she died a month later with severe subacute fibrosing alveolitis. It is believed that the lung disease was caused by sulphasalazine and that prednisolone was not able to prevent its development. A reversible form of lung disease has previously been attributed to this drug.
Functional Role of Matrix Metalloproteinase-8 in Stem/Progenitor Cell Migration and Their Recruitment Into Atherosclerotic Lesions
Authors: Qingzhong Xiao, Feng Zhang, Luyang Lin, Changcun Fang, Guanmei Wen, Tsung-Neng Tsai, Xiangyuan Pu, David Sims, Zhongyi Zhang, Xiaoke Yin, Binia Thomaszewski, Boris Schmidt, Manuel Mayr, Ken Suzuki, Qingbo Xu, Shu Ye
Journal: Circulation Research (2012)

Accumulating evidence indicates that stem/progenitor cells (SPCs) represent an important source of cells in atheromas and contribute to lesion formation and progression.We investigated whether matrix metalloproteinase-8 (MMP8) played a role in SPC migration and their recruitment into atheromas.We found that SPCs in atheromas expressed MMP8 and that MMP8 knockout significantly reduced SPC numbers in atherosclerotic lesions in apolipoprotein E (ApoE)-deficient mice fed a Western diet. Further in vivo experiments showed that ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(-/-) mice had fewer SPCs in atheromas and smaller lesions than ApoE(-/-)/MMP8(-/-) mice injected with stem cells isolated from bone marrows of ApoE(-/-)/MMP8(+/+) mice. Ex vivo experiments showed that MMP8 deficiency inhibited the ability of SPCs to migrate from the arterial lumen and the adventitia into atherosclerotic lesions. In vitro assays indicated that MMP8 facilitated SPC migration across endothelial cells and through Matrigel or collagen I. We also found that MMP8 cleaved a-disintegrin-and-metalloproteinase-domain-10 and that MMP8 deficiency reduced mature a-disintegrin-and-metalloproteinase-domain-10 on SPCs. Knockdown of MMP8 or incubation with the a-disintegrin-and-metalloproteinase-domain-10 inhibitor GI254023X decreased E-cadherin shedding on SPCs. The decrease in migratory ability of SPCs with MMP8 knockdown was reduced by incubation of such cells with culture supernatant from SPCs without MMP8 knockdown, and this compensatory effect was abolished by an antibody against soluble E-cadherin.MMP8 plays an important role in SPC migration and their recruitment into atherosclerotic lesions.
Coronary Heart Disease Mortality Is Actually Low in Diabetic Japanese by Direct Comparison With the Joslin Cohort
Authors: Toeko Matsumoto, Yasuo Ohashi, Nobuhiro Yamada, Masatoshi Kikuchi
Journal: Diabetes Care (1994)

OBJECTIVE To identify the mortality rate from coronary heart disease (CHD) in diabetic Japanese by directly comparing the Tokyo University Hospital cohort and the Joslin cohort using identical protocols. RESEARCH DESIGN AND METHODS Five hundred thirty-eight diabetic patients who were treated at Tokyo University Hospital with a 35- to 62-year age range at entry and with a diabetes duration of &amp;lt;5 years were followed retrospectively for more than 24 years. RESULTS The percentage of patients who survived at the end of the 24-year period was higher in the Tokyo University cohort (42%) than in the Joslin cohort (12%). The percentage of patients who died from CHD was remarkably lower in the Tokyo University cohort (11%) than in the Joslin cohort (39%). The CHD mortality rate was lower in the Tokyo University cohort than in the Joslin cohort, regardless of the duration of diabetes. CONCLUSIONS Our study confirmed the previous finding that the CHD mortality is lower in diabetic Japanese than in diabetic Caucasians.
The Great Psychologists from Aristotle to Freud
Authors: Lester S. King
Journal: JAMA (1964)

The educated physician should have more than a nodding acquaintance with the great thought of the past, and thinkers who have contributed to our understanding of the mind are well worth study. A survey of the great psychologists, from Aristotle to Freud, might have been a fascinating and rewarding volume that could greatly enlarge our insights. Unfortunately, this book leaves much to be desired. When the author is dealing with the very recent past, discussing such men as James, Hall, Titchener, Watson, Wertheimer, and Freud, there is a reasonable effectiveness. However, when the earlier writers are discussed —from Thales and Hippocrates up through the early 19th century, the result is disappointing. The author treats ancient periods from the viewpoint of modern knowledge, instead of trying to enter into the concepts of the times. In no way does he make vivid the environment and culture of historical eras, nor does he
Reporting Clinical Trial Results
Authors: Andrew L. Avins
Journal: Annals of Internal Medicine (1993)

Letters1 July 1993Reporting Clinical Trial ResultsAndrew L. Avins, MD, MPHAndrew L. Avins, MD, MPHSan Francisco General Hospital; San Francisco, CA 94105Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-119-1-199307010-00025 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The elegant study by Naylor and colleagues [1] is a valuable contribution to the debate over appropriate methods for reporting results. Several problems, however, complicate the rational incorporation of these findings into policy and clinical decision making.First, the short duration of most clinical trials may cause absolute differences to underestimate a potential true benefit. For example, suppose the intervention in the Helsinki Heart Study [2] entirely eliminated all coronary heart disease. This would have resulted in an absolute reduction of only 3.9% in the incidence of fatal and nonfatal myocardial infarctions, suggesting that this disease is ...References1. Naylor C, Chen E, Strauss B. Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness? Ann Intern Med. 1992; 117:916-21. Google Scholar2. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987; 317:1237-45. Google Scholar3. Anderson K, Wilson P, Odell P, Kannel W. An updated coronary risk profile. Circulation. 1991; 83:356-62. Google Scholar Author, Article, and Disclosure InformationAuthors: Andrew L. Avins, MD, MPHAffiliations: San Francisco General Hospital; San Francisco, CA 94105 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 July 1993Volume 119, Issue 1Page: 93-94KeywordsClinical trial reportingCoronary heart diseaseDecision makingForecastingLongitudinal studiesMyocardial infarctionPrevention, policy, and public healthPreventive medicineQuality of lifeRelative risk ePublished: 15 August 2000 Issue Published: 1 July 1993 Copyright & PermissionsCopyright © 1993 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
THE EVALUATION AND TREATMENT OF DISTURBED LIVER FUNCTION
Authors: C. W. McCLURE
Journal: JAMA (1925)

In the present communication we outline some of the principal results of correlated studies on the functional state of the liver of the lower animals and of man. The studies include both means for ascertaining the state of liver function and means for influencing that state. In man the state of liver function was determined by estimating the concentrations of cholesterol, bile acids, total pigments and bilirubin of duodenal contents. These contents were obtained both from normal controls and from patients with various diseases including lesions of the liver or its ducts. The studies on animals will be reported in detail at a later date.  It is well established that the liver performs a number of functions of foremost importance to the economy of the organism. It converts protein products absorbed from the intestines into urea. It detoxifies poisons that come to it from a variety of sources. It excretes
Experiments on Animals
Authors: W. Tyldesley
Journal: BMJ (1961)

<h3>Background</h3> Glomus tumours are benign painful tumours of the glomus body, a thermoregulatory shunt in the digits. Glomus tumours of the fingers and toes are associated with the monogenic disorder neurofibromatosis type 1 (NF1) and are recently recognised as part of the NF1 phenotype. <h3>Methods and Results</h3> A multi-institutional experience with 15 individuals with NF1 and glomus tumours of the fingers or toes is reported. The majority of individuals presented with at least two of the symptoms in the classic triad of localised tenderness, severe paroxysmal pain, and sensitivity to cold. Appearance of the nail and finger or toe is often normal. Women are affected more often than men. Multifocal tumours are common. There is often a delay in diagnosis of many years and clinical suspicion is key to diagnosis, although magnetic resonance imaging may be useful in some scenarios. Surgical extirpation can be curative; however, local tumour recurrence and metachronous tumours are common. Three of our patients developed signs and symptoms of the complex regional pain syndrome. <h3>Conclusions</h3> Glomus tumours in NF1 are more common than previously recognised and NF1 patients should be specifically queried about fingertip or toe pain.
Counseling in Medical Genetics
Authors: Raymond L. Teplitz
Journal: JAMA (1981)

A book full of errors, incomplete discussions, omissions, and commissions should be easy to review. And yet, it is not. This is because Dr Reed combines these faults with some real assets, which are easy readability (with occasional lapses into jargon) and a style comprehensible to the family physician, the apparent target of the book. The unevenness of the text can be seen in examples from chapter 11 on "Blood Genetics." A frequent characteristic is that of inadequate or complete lack of explanation of a statement that clearly calls for explanation. On page 82, the author states that heterozygotes for sickle cell anemia (Hb A/S) make more HbA than HbS. Why? Later (page 84), reference to restriction analysis for prenatal diagnosis of sickle cell anemia as a "method to study the hemoglobin chains," instead of hemoglobin genes, is misleading. The bibliography cites Panney et al (1979), with no mention of
Regulation of Granulopoiesis
Authors: David W. Golde, Martin J. Cline
Journal: New England Journal of Medicine (1974)

CIRCULATING phagocytic cells are crucial elements in the host's defense against microbial invasion. The cell type of greatest consequence in this function is the mature neutrophil, although mononuclear phagocytes (monocytes and macrophages) also play an important part.1 , 2 Neutrophilic granulocytes originate from precursor cells in the bone marrow. Their production is regulated by homeostatic mechanisms that, under normal circumstances, maintain the numbers of circulating neutrophils within a narrowly defined range. The average granulocyte (taken here to mean neutrophilic granulocyte although, in the strict sense, the term encompasses the eosinophils and basophils as well) production rate for man is estimated at 1.6 . . .