tbuckley/cabot-search huggingface dataset:
1000. Down-Regulating the Epithelial Glycoprotein-2 Promoter Utilizing Engineered Zinc Finger Protein Transcription Factors
Authors: Willemijn M. Gommans, Pamela M.J. McLaughlin, Robbert Cool, Beatrice I. Lindhout, Bert van der Zaal, Hidde J. Haisma, Marianne G. Rots
Journal: Molecular Therapy (2006)

Top of pageAbstract
Engineered zinc finger protein transcription factors (ZFP-TFs) are emerging as novel powerful tools to regulate endogenous gene expression. Zinc finger proteins consist of modular building blocks, with each domain recognizing 3-4 base pairs. Stitching these modular domains together results in the recognition of an extended DNA sequence, increasing the specificity of the target sequence. Specific amino acid positions within each domain recognize the DNA. Altering the amino acid residues at these positions therefore results in the recognition of different base pairs. A wide variety of effector domains can be attached to the DNA-binding zinc finger protein, for example to activate or inhibit gene transcription. In this study we utilized engineered ZFP-TFs to specifically inhibit the expression of the epithelial glycoprotein-2 (EGP-2).

EGP-2 is expressed in the most prevalent types of carcinomas, including breast, ovarian, and colon cancer. Recently, others have demonstrated that down-regulation of EGP-2 using siRNA or ODNs resulted in a decrease in the migration, invasion, and proliferation potential of tumor cells. Therefore, inhibiting the expression of EGP-2 can provide a novel anti-cancer treatment for a broad range of tumor types.

Down-regulating EGP-2 expression by targeting the mRNA requires the targeting of many molecules. Direct down-regulation of the EGP-2 expression at the DNA level using engineered ZFP-TFs can therefore be more effective. We engineered a zinc finger protein that specifically bound to a 9 base-pair target sequence in the EGP-2 promoter sequence. After attaching a gene-expression inhibition domain to the DNA-binding ZFP, co-transfection of EGP-2-positive cells with a plasmid expressing the engineered ZFP-TF and a plasmid containing the luciferase gene under the control of the EGP-2 promoter resulted in 60% inhibition of luciferase expression. To further increase the specificity for binding to the EGP-2 promoter, we engineered three different ZFP-TFs targeting 18 base pair sequences within the EGP-2 promoter. Co-transfection experiments demonstrated that the engineered ZFP-TFs caused up to 80% down-regulation of the EGP-2 promoter while no down-regulation of a non-target promoter was observed. Combining inhibition at the DNA level with inhibition at the RNA level using siRNA might even further enhance the down-regulation of EGP-2 promoter activity.

In this study we have demonstrated that ZFP-TFs can be engineered to down-regulate the EGP-2 promoter, generating a novel therapeutic for the treatment of a broad variety of tumor types.
843-4 Reduction in late loss and restenosis in patients with small vessels treated with the slow rate-release, polymer-based paclitaxel-eluting stent: Results from TAXUS-IV
Authors: Gregg W Stone, Stephen G Ellis, Charles O'Shaughnessy, James Tift Mann, Mark Turco, Albert Raizner, Louis Cannon, Michael Kutcher, Paul Gurbel, S.Chiu Wong, Mary E Russell, Jeffrey J Popma
Journal: Journal of the American College of Cardiology (2004)
Organ Survey Through Digitized Imaging Value in Detection of a Splenic Rupture
Authors: HANS J. NERDRUM
Journal: Clinical Nuclear Medicine (1982)

The rapidly updated display of scintigraphic images processed by a computer system and used for positioning is of high quality and may be used to do a quick survey of an organ. The value of this in a preliminary investigation is illustrated by a case of a patient with a splenic rupture. The information obtained through the preliminary survey contributed significantly to the correct diagnosis. Diagnostic reliability may be improved by inclusion of this procedure in scintigraphic investigations, especially in emergency situations.
Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer
Authors: Antonio Jimeno, Aik Choon Tan, Jordy Coffa, N.V. Rajeshkumar, Peter Kulesza, Belen Rubio-Viqueira, Jenna Wheelhouse, Begoña Diosdado, Wells A. Messersmith, Christine Iacobuzio-Donahue, Anirban Maitra, Marileila Varella-Garcia, Fred R. Hirsch, Gerrit A. Meijer, Manuel Hidalgo
Journal: Cancer Research (2008)

Abstract The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development. [Cancer Res 2008;68(8):2841–9]
KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia
Authors: K Malinowska-Ozdowy, C Frech, A Schönegger, C Eckert, G Cazzaniga, M Stanulla, U zur Stadt, A Mecklenbräuker, M Schuster, D Kneidinger, A von Stackelberg, F Locatelli, M Schrappe, M A Horstmann, A Attarbaschi, C Bock, G Mann, O A Haas, R Panzer-Grümayer
Journal: Leukemia (2015)

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18–30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.
The scientific meeting
Authors: David Isaacs, Stephen Isaacs, Dominic Fitzgerald
Journal: BMJ (2006)

The main purpose of a scientific meeting is globalisation. To a doctor, globalisation means visiting the globe. Travel broadens your mind, adds to your Frequent Flyer points, and protects you from minor irritations such as patients and family. 

A hefty registration fee ensures the meeting's profitability. It is widely acknowledged that doctors are not expected to pay for their education, but are generous enough to let drug companies do so. Drug companies will also organise the meeting, no strings attached. It is indeed …
Clinical study of peanut and nut allergy in 62 consecutive patients: new features and associations
Authors: P. W Ewan
Journal: BMJ (1996)

To investigate clinical features of acute allergic reactions to peanuts and other nuts.Analysis of data from consecutive patients seen by one doctor over one year in an allergy clinic at a regional referral centre.62 patients aged 11 months to 53 years seen between October 1993 and September 1994.Type and severity of allergic reactions, age at onset of symptoms, type of nut causing allergy, results of skin prick tests, and incidence of other allergic diseases and associated allergies.Peanuts were the commonest cause of allergy (47) followed by Brazil nut (18), almond (14), and hazelnut (13). Onset of allergic symptoms occurred by the age of 2 years in 33/60 and by the age of 7 in 55/60. Peanuts accounted for all allergies in children sensitised in the first year of life and for 82% (27/33) of allergies in children sensitised by the third year of life. Multiple allergies appeared progressively with age. The commonest symptom was facial angioedema, and the major feature accounting for life threatening reactions was laryngeal oedema. Hypotension was uncommon. Of 55 patients, 53 were atopic--that is, had positive skin results of tests to common inhaled allergens--and all 53 had other allergic disorders (asthma, rhinitis, eczema) due to several inhaled allergens and other foods.Sensitisation, mainly to peanuts, is occurring in very young children, and multiple peanut/nut allergies appear progressively. Peanut and nut allergy is becoming common and can cause life threatening reactions. The main danger is laryngeal oedema. Young atopic children should avoid peanuts and nuts to prevent the development of this allergy.
Dealing with uncertainty: perspective from primary care
Authors: Anthony Harnden
Journal: BMJ (2006)

ing will be a more difficult problem to overcome.It may even be difficult to maintain the normal level of intensive care because of a shortage of appropriately trained staff.It is predicted that 25-50% of the population will become infected with influenza during the epidemic, and experience from the epidemic of severe acute respiratory syndrome (SARS) has shown that critical care staff are at particularly high risk of infection. 3The numbers of experienced critical care staff will inevitably be depleted, and agency staff will be unable to make up the deficiency of trained staff.
Bright-Field Dual-Color Chromogenic In Situ Hybridization for Diagnosing Echinoderm Microtubule-Associated Protein-Like 4-Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinomas
Authors: Akihiko Yoshida, Koji Tsuta, Hiroaki Nitta, Yutaka Hatanaka, Hisao Asamura, Ikuo Sekine, Thomas M. Grogan, Masashi Fukayama, Tatsuhiro Shibata, Koh Furuta, Takashi Kohno, Hitoshi Tsuda
Journal: Journal of Thoracic Oncology (2011)
Role of the Community Teaching Hospital in Graduate Medical Education
Authors: Philip D. Herrick
Journal: JAMA (1962)

It has been well established that the community teaching hospital is capable of providing the highest type of training for interns and residents. The maintenance of such an educational program in a community hospital demands a curriculum of minimal standards, an active teaching faculty for implementation, and an organized method for program evaluation and maintenance of proper standards. Because of these increasing demands that an active teaching program makes upon the participating hospital, the traditional organizational structure of the community hospital must change. A reorganization of the intern-resident teaching program around full-time teaching department heads and maintenance of some form of active medical school affiliation would appear to be necessary for future growth and development of the successful community teaching hospital.
Role of mitochondrial re-energization and Ca influx in reperfusion injury of metabolically inhibited cardiac myocytes
Authors: G RODRIGO, N STANDEN
Journal: Cardiovascular Research (2005)

We used isolated myocytes to investigate the role of mitochondrial re-energization and Ca2+ influx during reperfusion on hypercontracture, loss of Ca2+ homeostasis and contractile function.Isolated adult rat ventricular myocytes were exposed to metabolic inhibition (NaCN and iodoacetate) and reperfusion injury was assessed from hypercontracture, loss of Ca2+ homeostasis ([Ca2+]i measured with fura-2) and failure of contraction in response to electrical stimulation. Mitochondrial membrane potential was followed using the potentiometric dye tetramethylrhodamine ethyl ester.Metabolic inhibition led to contractile failure and rigor accompanied by a sustained increase in [Ca2+]i. Reperfusion after 10 min metabolic inhibition led to an abrupt repolarization of the mitochondrial membrane potential (after 25.5+/-1.2 s), a transient fall in [Ca(2+]i followed by an abrupt hypercontracture (37.1+/-1.8 s) in 84% of myocytes. Ca2+ homeostasis (diastolic [Ca2+]i < 250 nM) recovered in only 23.3+/-5.1% of cells and contractions recovered in 15.3+/-2.2%. Oligomycin abolished the hypercontracture on reperfusion, but mitochondrial repolarization was unaffected. Preventing Ca2+ influx during reperfusion with [Ca2+]i-free Tyrode or with an inhibitor of Na(+)/Ca2+ exchange did not prevent the hypercontracture, but increased the percentage of cells recovering Ca2+ homeostasis and contractile function. The presence of 0.5 microM cyclosporin A did not prevent hypercontracture but increased the percentage of cells recovering Ca2+ homeostasis to 56.2+/-3.6% and contractile function to 52+/-4.3%.Reperfusion-induced hypercontracture, and loss of Ca2+ homeostasis and contractile function are initiated following mitochondrial re-energization. The hypercontracture requires the production of oxidative ATP but not Ca2+ influx during reperfusion. Loss of Ca2+ homeostasis and contractile function are linked to Ca2+ influx during reperfusion, probably via opening of mitochondrial permeability transition pores.
Peter Gordon Cochrane Robertson
Authors: A. J Parkin
Journal: BMJ (2009)

Following house jobs, Peter Gordon Cochrane Robertson secured a research scholarship at the Alfred Hospital, Melbourne, Australia, studying mammalian cardiovascular physiology. He returned to Dundee as a cardiology registrar working with Professor Sir Iain Hill. In 1969 he moved to Newark to follow a career in general practice at the Lombard Street surgery, where he worked in partnership until his retirement in 1995. …
Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure
Authors: Katsuji Imai, Hideyuki Sato, Masatsugu Hori, Hideo Kusuoka, Hitoshi Ozaki, Hiroshi Yokoyama, Hiroshi Takeda, Michitoshi Inoue, Takenobu Kamada
Journal: Journal of the American College of Cardiology (1994)
Goodpasture's Syndrome Associated with Influenza A2 Virus Infection
Authors: CURTIS B. WILSON
Journal: Annals of Internal Medicine (1972)

A woman developed severe hemoptysis and glomerulonephritis (Goodpasture's syndrome) in association with an apparent influenza A2 virus infection. The proliferative glomerular lesion contained immunofluorescent deposits of immunoglobulin and complement in a linear pattern along the glomerular basement membrane (GBM), suggesting the presence of anti-GBM antibodies. The pulmonary and renal functional abnormalities rapidly diminished and were absent on examination 5 years after the original illness. This suggested that the response was short-lived and may have been triggered by a transient, virally associated antigenic stimulus.
Levodopa and Melanoma
Authors: Peyton Delaney
Journal: JAMA (1979)

<h3>To the Editor.—</h3> Based on personal experience with a single case of Parkinson's disease and malignant melanoma and an incomplete review of the literature, Sober and Wick (240:554, 1978) conclude that levodopa should be administered to patients with Parkinson's disease who have a history of melanoma. This recommendation is particularly sobering in view of their own studies.<sup>1</sup> Three additional cases of the combination of malignant melanoma and Parkinson's disease have been reported.<sup>2,3</sup>In two, surgical excision of the melanomas was accomplished before the onset of Parkinson's disease, and neither patient was treated with levodopa. The third patient's condition was diagnosed as malignant melanoma eight years after treatment with levodopa and four years after treatment with levodopa and methyldopa. All three have now been treated for periods in excess of six months with bromocriptine, and although therapy had to be terminated in one patient because of centrally mediated complications of
[219] NATURAL HISTORY OF SPONTANEOUS BACTERIAL PERITONITIS: A LONGITUDINAL STUDY IN 263 CIRRHOTIC PATIENTS AFTER THE FIRST ASCITES DECOMPENSATION
Authors: N. Canete, E. Erice, A. Bargallo, I. Cirera, H. Masnou, M. Miquel, S. Coll, M.D. Gimenez, J.A. Galeras, R.M. Morillas, R. Planas, R. Sola
Journal: Journal of Hepatology (2007)
Hearts That Go Thump in the Night
Authors: Kenneth B. Desser, Artur DeSa'Neto, Alberto Benchimol
Journal: New England Journal of Medicine (1979)

IT is common for a patient to perceive his heartbeat by hearing cardiac sounds when the side of his head is placed on a pillow at night.1 Indeed, most physicians are familiar with complaints of precordial "thumping" or "pounding" when a subject reclines on the left side. In most cases these nocturnal sensations are not based on serious disturbances of heart rhythm. The purpose of this report is to describe a striking exception to this time-honored impression.Case ReportA 59-year-old woman was seen because of the chief complaint of "heart pounding" when she turned to her left side after . . .
Hyperreninemic hypoaldosteronism after chronic stress in the rat.
Authors: G Aguilera, A Kiss, B Sunar-Akbasak
Journal: Journal of Clinical Investigation (1995)

The effects of chronic stress on the renin-angiotensin-aldosterone system were studied by analysis of plasma hormone levels, kidney renin mRNA levels, adrenal angiotensin II receptors, and steroidogenesis in rats subjected to repeated immobilization (2 h daily) or intraperitoneal injections of 1.5 M NaCI for 14 d. 24 after the last stress in both stress models, plasma aldosterone levels were reduced in spite of significant increases in plasma renin activity. Repeatedly intraperitoneal hypertonic saline-injected rats showed plasma renin activity responses to acute immobilization similar to controls, but markedly reduced plasma aldosterone responses. Concomitant with the increases in plasma renin activity, renin mRNA levels in the kidney were significantly increased in intraperitoneal hypertonic saline-injected rats, and these increases were prevented by beta-adrenergic receptor blockade with propranolol. In isolated adrenal glomerulosa cells from chronically stressed rats, maximum aldosterone responses to angiotensin II, ACTH, and 8-Br-cAMP were significantly decreased, whereas pregnenolone responses were increased. P450-aldosterone synthetase mRNA levels and binding of 125I-[Sar1,Ile8] angiotensin II were significantly reduced in the adrenal zona glomerulosa of stressed rats. These studies show that chronic repeated stress leads to renin stimulation due to sympathetic activation, and inhibition of aldosterone secretion due to inhibition of the late steroidogenic pathway. The data provide evidence for a role of chronic stress in the development of hyperreninemic hypoaldosteronism.
THE ACTION OF CORTISONE ACETATE ON CELL-MEDIATED IMMUNITY TO INFECTION
Authors: Robert J. North
Journal: The Journal of Experimental Medicine (1971)

Pulse labeling with tritiated thymidine shows that the response in the mouse to infection with L. monocytogenes includes a large increase in the division of lymphoid cells in the spleen, an increase in the division of macrophages in the liver, and an accumulation of monocyte-derived macrophages at infective foci in the tissues. A single 2.5 mg dose of cortisone acetate given at the beginning of infection greatly delays and suppresses these three components of the host response. The unrestricted bacterial multiplication which follows cortisone treatment is ultimately because of a failure of monocyte-derived macrophages to accumulate at infective foci where they normally express immunity. The accumulation of polymorphs at these sites, in contrast, is enhanced. It is argued that cortisone acetate prevents the accumulation of monocytes at infective foci indirectly by suppressing the production in the spleen of immunologically-committed lymphocytes which are needed to mediate the cellular events at infective foci.
Jeremy Hugh Baron: a tribute from a colleague and friend
Authors: J. Bennett
Journal: BMJ (2015)

Hugh Baron’s foremost quality was his love of scholarship. He hungered for knowledge in all his many areas of interest, and added to most of them. He described his hobby as “looking,” and from his tall, gaunt frame his quizzical gaze would peruse scientific data, paintings, buildings, and members of committees alike. Many were found wanting. He was a compulsive writer and publisher: everything (he believed) should be recorded. As well as his many interests in gastroenterology he had clear views on ethical matters and was always concerned about the “political” aspects of medicine. He was strong on medical history, and on art in, and out of, hospitals. In later years he wrote thoughtfully about religious matters in a collection of talks given to seminars at his synagogue in New York.

His father was a general practitioner in Tottenham, north London. Hugh won a scholarship to University College School, then a Styring scholarship to Queens College, Oxford (where he graduated BA), and was the first Broderipp scholar at Middlesex Hospital medical school, achieving BM, B Ch. After house officer posts at the Middlesex and Royal Northern hospitals, national service claimed him for the Royal Army Medical Corps as captain. At the Royal Herbert Hospital, Woolwich, he passed MRCP and was sent as a junior specialist to Malaya. He might have ended his life there had his commanding officer not ordered him to stay in Kuala Lumpur, rather than …
London's ethnic minority groups have poorer health, report shows
Authors: Lynn Eaton
Journal: BMJ (2004)

A report from the London Health Commission shows how the capital's black and ethnic minority communities are more likely to have poorer health than white groups; this is a finding based on 10 health indicators, including life expectancy, housing, and crime.

It is the third report on health compiled by the London Health Commission, which was set up by the mayor of London in 2000 to improve the health and wellbeing of Londoners. The report is published in collaboration with the Greater London Authority and the London Health Observatory, one of nine …