tbuckley/cabot-search huggingface dataset:
A Designed Zinc-finger Transcriptional Repressor of Phospholamban Improves Function of the Failing Heart
Authors: H Steve Zhang, Dingang Liu, Yan Huang, Stefan Schmidt, Reed Hickey, Dmitry Guschin, Haili Su, Ion S Jovin, Mike Kunis, Sarah Hinkley, Yuxin Liang, Linda Hinh, S Kaye Spratt, Casey C Case, Edward J Rebar, Barbara Ehrlich, Philip D Gregory, Frank J Giordano
Journal: Molecular Therapy (2012)

Selective inhibition of disease-related proteins underpins the majority of successful drug–target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repressor as therapy for heart failure, and provide evidence that delivery of engineered ZFP TFs to native organs can drive therapeutically relevant levels of gene repression in vivo. Given the adaptability of designed ZFPs for binding diverse DNA sequences and the ubiquity of potential targets (promoter proximal DNA), our findings suggest that engineered ZFP repressors represent a powerful tool for the therapeutic inhibition of disease-related genes, therefore, offering the potential for therapeutic intervention in heart failure and other poorly treated human diseases. Selective inhibition of disease-related proteins underpins the majority of successful drug–target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repressor as therapy for heart failure, and provide evidence that delivery of engineered ZFP TFs to native organs can drive therapeutically relevant levels of gene repression in vivo. Given the adaptability of designed ZFPs for binding diverse DNA sequences and the ubiquity of potential targets (promoter proximal DNA), our findings suggest that engineered ZFP repressors represent a powerful tool for the therapeutic inhibition of disease-related genes, therefore, offering the potential for therapeutic intervention in heart failure and other poorly treated human diseases.
Cuts to the Office for National Statistics will damage the health of the nation
Authors: M. Hobday
Journal: BMJ (2013)

In his article protesting against proposed cuts to outputs from the Office for National Statistics, Hawkes argues that statistics are the lifeblood of policy.1 He’s right, of course, but it is not just policy that will suffer if we lose these data: ultimately people will.

For example, one year and five year cancer survival by age for England, an output at risk, provides Macmillan Cancer Support with unique information on …
Abstract 1001: Reductive tricarboxylic acid metabolism of glutamine mediates lipogenesis under hypoxia
Authors: Christian Metallo, Paulo Gameiro, Matthew Vander Heiden, Othon Ilioupoulos, Greg Stephanopoulos
Journal: Cancer Research (2012)

Abstract Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and adenosine triphosphate citrate lyase (ACL) in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle (TCA) and fatty acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and utilization of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells employ reductive metabolism of alpha-ketoglutarate (aKG) to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase 1 (IDH1) dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived aKG for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau (VHL) tumor suppressor protein preferentially utilize reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon utilization in order to produce AcCoA and support lipid synthesis in mammalian cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1001. doi:1538-7445.AM2012-1001
Aspirin—A Dangerous Drug?
Authors: Harvey J. Weiss
Journal: JAMA (1974)

THE medicinal value of leaves and bark now known to contain salicylates was observed by Hippocrates, and numerous references to the analgesic properties of these plant materials may be found in the literature of the middle ages.<sup>1</sup>In 1829, Leroux isolated the active ingredient of the willow bark and identified it as a glucoside, salicin. Salicylic acid was prepared from the latter by Piria in 1838, and the acetic acid ester, acetyl salicylic acid, was synthesized by von Gerhardt in 1853. The name aspirin was formed from contractions of the terms "acetyl" and<i>Spirsäure</i>, the latter referring to the genus<i>Spiraea</i>, one of the botanical sources from which salicylic acid was obtained. Aspirin, generally available as powders, was introduced into medicinal practice in Germany before the turn of the century, and the tablet form was introduced into the United States in 1915. It has since become the most widely
Cd8+ T Cells Can Block Herpes Simplex Virus Type 1 (HSV-1) Reactivation from Latency in Sensory Neurons
Authors: Ting Liu, Kamal M. Khanna, XiaoPing Chen, David J. Fink, Robert L. Hendricks
Journal: The Journal of Experimental Medicine (2000)

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8+ T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8α monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8+ T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8+ T cells aborting virion production.
P4-12-10: A Prospective Study of Physical Activity Patterns and Changes in Breast Cancer Patients during Active Breast Cancer Treatment.
Authors: I-R Kim, E-K Choi, S-J Nam, J Lee, S-K Lee, J Yang, DY Noh, W Han, J Cho
Journal: Cancer Research (2011)

Abstract Purpose Physical activity (PA) has been shown to benefit cancer patients’ physical functioning, emotional well-being, and symptom management. Moderate PA may reduce the side effects of breast cancer treatment and improve quality of life, but most of the studies have been conducted after active treatment was completed and there is little data on patterns of PA during active treatment. This study aims to evaluate patterns and changes in physical activity among breast cancer patients during active treatment. Patients and Methods We recruited 411 women with non-metastatic breast cancer between July 2010 and Dec 2010 from two major cancer hospitals in Seoul, Korea. Trained researchers interviewed participants at enrollment (before surgery), and at 2 weeks, 3 months, and 6 months post surgery. Intensity and duration of PA were assessed using the Minnesota Leisure Time Physical Activity Questionnaire, and energy expenditure (the average calories spent per day) was calculated as metabolic equivalents (METs). Quality of life (EORTC), fatigue (BFI), socio-demographic and clinical characteristics were also assessed. After excluding 15 patients with recurrence during follow-up and 65 patients were lost to follow-up, the final sample size was 331 patients (80.5%). Results The mean (SD) age and BMI of study participants were 46.4 years and 23.3kg/m2 (SD 3.35). 83.7% of women had lumpectomy, and 70.6% and 85.9% had adjuvant chemotherapy and radiotherapy respectively. Breast cancer patients were most likely to spend their energy in lifestyle (walking and driving) and leisure (shopping, reading, and watching TV) activities but spent little energy in sport activities (Table). Conclusion PA declined after the surgery and gradually recovered at 3 and 6 months post surgery but it did not return to the baseline level. Breast cancer patients may need encouragement and support to perform more intensive physical activities during active treatment. *Acknowledgement: The research was accomplished by the support from AMOREPACIFIC and Korea Breast Cancer Foundation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-10.
Successful Protection of Humans Exposed to Rabies Infection
Authors: Mahmoud Bahmanyar
Journal: JAMA (1976)

Forty-five persons severely bitten by rabid dogs and wolves in Iran were treated after exposure with a new rabies vaccine produced in cultures of human diploid cells. All except one also received one injection of rabies immune serum. This treatment, in contrast to past experience with other vaccines, resulted in protection of all individuals against rabies. Thus, almost a century after the postexposure treatment of humans was initiated, an effective tool for protecting man against rabies has finally been developed. (<i>JAMA</i>236:2751-2754, 1976)
Establishment of a cell line of human skin squamous cell carcinoma in vitro
Authors: S. KONDO, K. ASO
Journal: British Journal of Dermatology (1981)

A cell line of a squamous cell carcinoma of human skin (HSC-I) has been established in vitro, and successfully maintained proliferative in continuous tissue culture for about 2 1/2 years since March 1978. Another cell line (HSC-Ib) has been established in vitro from the recurrence of the same cancer. It has been maintained for about 8 months since December 1979. 3T3 feeders were used in the initial cultures in both cases. The cells grow in a monolayer in vitro and are epithelioid with anaplastic features. Chromosome analysis of HSC-I, frozen and thawed HSC-I, the transplanted tumour in a nude mouse and HSC-Ib all showed hypotetraploidy with the modal number 80, which reconfirms that HSC-I derives from the original skin tumour. The cell line is available to other investigators.
Effect of Hexamethonium Iodide on Gastric Secretion and Motility
Authors: A. W. Kay, A. N. Smith
Journal: BMJ (1950)

PENTAMETHONlUM AND HEXAMETHONIUM IODIDEIt was relieved in two to four minutes by lying down or walking about, but its presence limits the therapeutic value of these drugs.It was established that a different response.was obtained in upper and lower limbs with the drugs in the doses used in this study.In the lower limbs a rapid and prolonged increase in blood flow and skin temperature occurred after C5 and C6.This approximated closely to that obtained by reflex vasodilatation, and these drugs may therefore be of value in the investigation of peripheral vascular disease in the legs.However, in the upper limbs no significant increases in skin temperature or blood flow occurred in 18 out of 31 tests with C5, and in 16 out of 31 tests with C6; in the remainder the increase in blood flow or skin temperature was slight and in no way comparable to that obtained by reflex vasodilatation.These drugs are therefore unlikely to be useful in the investigation of vasospastic conditions in the upper limb.In the dosage used the vasodilator effect of both C5 and C6 on the lower limb was much greater and more constant than that of T.E.A.B., and the side-effects of C5 and C6 were more pleasant for the patient.Blood flow to muscle, measured by estimation of forearm blood flow, was not greatly altered.Sweating was diminished in those digits in which temperature rose.We wish to record our thanks to Professor Sir James Learmonth and to Mr. D. M
Training More Generalists
Authors: Irwin J. Schatz
Journal: Annals of Internal Medicine (1994)

Letters1 January 1994Training More GeneralistsIrwin J. Schatz, MDIrwin J. Schatz, MDResidency Review Committee for Internal Medicine; Honolulu, HI 96813Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-120-1-199401010-00029 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Dr. Rivo's contribution is timely and important [1]. However, his statement that “the Special Requirements (for Internal Medicine Training) only call for 10% continuity-of-care experience,” is not a direct quotation from the special requirements, and probably represents his interpretation of the language. As such, it may mislead many readers.The current Special Requirements state that “at least 25 percent of the three years of residency training must be in the ambulatory care setting,” to include “first contact, comprehensive and continuing care … through at least two of the three years …” [2]. The new Special Requirements, effective ...REFERENCE1. Rivo M. Internal medicine and the journey to medical generalism. Ann Intern Med. 1993; 119:146-52. Google Scholar2. American Medical Association. Special requirements for internal medicine training. In: Directory of Graduate Medical Education Programs: 1992-93. Chicago: American Medical Association; 1993. Google Scholar Author, Article, and Disclosure InformationAuthors: Irwin J. Schatz, MDAffiliations: Residency Review Committee for Internal Medicine; Honolulu, HI 96813 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 January 1994Volume 120, Issue 1Page: 92-93KeywordsPatientsResidency ePublished: 15 August 2000 Issue Published: 1 January 1994 Copyright & PermissionsCopyright © 1994 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Significance of the Simultaneous Occurrence of Connective Tissue Disease and Agammaglobulinaemia
Authors: J. Rotstein, R. A. Good
Journal: Annals of the Rheumatic Diseases (1962)

During the past 6 years Good and his co-workers have made extensive studies of 37 patients with agammaglobulinaemia.Eighteen are male children with the congenital form of the disease, and nineteen are adults of both sexes with acquired agammaglobulinaemia.The classical criteria of the disease, an absence of gamma globulin and circulating antibody secondary to the lack of plasma cells, were present in all these patients.Some of those with agammaglobulinaemia also show abnormalities in the beta-2 globulins.When the amount of gamma globulin in the agammaglobulinaemic patients was measured by immunochemical methods, it was found that none had an absolute lack of gamma globulin, but all had it in only minute amounts.The congenital cases have less than the acquired ones; the lowest amount found was I mg.per cent.An observation which has been of extreme interest to us has been the occurrence of connective tissue disease in twelve (one-third) of our patients.Rheu- matoid arthritis, atypical arthritis, and tenosynovitis resembling rheumatoid arthritis, and one case of diffuse fibrinoid disease involving the blood vessels throughout the body has been found in these twelve patients.Dermatomyositis, juvenile rheumatoid arthritis, and scleroderma have been reported in agammaglobulinaemic patients in the literature (Good and Varco, 1955; Bruton, 1952; Hayles, Stickler, and McKenzie, 1954; Grant and Wallace, 1954; Van Gelder, 1957; Hanson, 1961).Of our twelve patients with connective tissue disease, eight have classical rheumatoid arthritis, according to the diagnostic criteria of the American Rheumatism Association (Table, opposite).Six are adults with the acquired form of the disease and
Supraventricular Arrhythmia in the Elderly
Authors: Harold L. Karpman
Journal: JAMA (1971)

To the Editor.—  We read with interest the article entitled, Refractory Supraventricular Arrhythmias in the Elderly: Treatment with Permanent Demand Pacing and Cardiac Drugs (215:589-594, 1971).  In their synopsis-abstract, Beller et al indicated that recurrent episodes of bradycardia and asystole have been totally eliminated and supraventricular tachycardia has not recurred as long as the patients have continued their medication.  It is absolutely impossible to make a statement of this nature without utilizing dynamic electrocardiography (Holter) as an objective method for evaluating the presence or absence of atrial or ventricular arrhythmias or both. The standard resting ECG only records between 60 and 100 cardiac cycles, whereas a ten-hour dynamic ECG may record as many as 50,000 to 60,000 cardiac cycles. We have performed over 1,700 ten-hour dynamic ECGs and have detected numerous episodes of intermittent pacemaker malfunction which had not been detected by ordinary clinical means since the patients were usually
Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus
Authors: Stacy L Musone, Kimberly E Taylor, Timothy T Lu, Joanne Nititham, Ricardo C Ferreira, Ward Ortmann, Nataliya Shifrin, Michelle A Petri, M Ilyas Kamboh, Susan Manzi, Michael F Seldin, Peter K Gregersen, Timothy W Behrens, Averil Ma, Pui-Yan Kwok, Lindsey A Criswell
Journal: Nature Genetics (2008)
Internet-Delivered Treatment for Substance Abuse: A Multisite Randomized Controlled Trial
Authors: Aimee N.C. Campbell, Edward V. Nunes, Abigail G. Matthews, Maxine Stitzer, Gloria M. Miele, Daniel Polsky, Eva Turrigiano, Scott Walters, Erin A. McClure, Tiffany L. Kyle, Aimee Wahle, Paul Van Veldhuisen, Bruce Goldman, Dean Babcock, Patricia Quinn Stabile, Theresa Winhusen, Udi E. Ghitza
Journal: American Journal of Psychiatry (2014)

The Therapeutic Education System, which combines skills-oriented counseling and contingency management in an Internet-delivered behavioral intervention, produced high rates of abstinence from drugs and heavy drinking among patients with a good prognosis (those who entered the study with positive urine drug or breath alcohol screen) but doubled the likelihood of abstinence among patients with an otherwise poor prognosis.
Polypectomy in the Presence of Portal Hypertension - An Increased Risk of Bleeding?
Authors: G. Winter, F. Trux, D. Müting, K. Elster, H. Koch
Journal: Endoscopy (1983)

A report is presented on 58 polypectomies performed in the stomach and colorectum in 46 patients. Twenty-five patients had portal hypertension consequent on liver cirrhosis, while 21 patients had healthy livers. The question as to whether haemorrhage occurred immediately after polypectomy or within the next 24 hours, was investigated. Furthermore, either the stalk (of pedunculated polyps), or the polyp itself (when sessile) was investigated pathologically-anatomically, with respect to its vascularity pattern. The submucosal and intramucosal vascularity patterns were classified in 4 categories, I to IV. A tentative interpretation of the results obtained indicates, on the basis of their mucosal and submucosal vascularity patterns, that patients with portal hypertension developing from a cirrhosis of the liver, are not at any higher risk of haemorrhage than patients with no portal hypertension.
Ataxia-Telangiectasia: A Multisystem Hereditary Disease with Immunodeficiency, Impaired Organ Maturation, X-Ray Hypersensitivity, and a High Incidence of Neoplasia
Authors: THOMAS A. WALDMANN
Journal: Annals of Internal Medicine (1983)

Ataxia-telangiectasia is an autosomal, recessive, multisystem disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, recurrent sinopulmonary infections, high incidence of neoplasia, and variable immunodeficiency. Synthesis of antibodies and certain immunoglobulin subclasses is disrupted, due to disorders of B-cell and helper-T-cell function. Patients have various disorders of cell-mediated immunity, including an inability to produce antigen-specific cytotoxic lymphocytes to viral pathogens. Ataxia-telangiectasia is associated with disorders of cell growth and chromosomal integrity as well as an increased sensitivity to certain chemical and physical agents, including ionizing irradiation, and potential abnormalities in DNA repair mechanisms. Patients have an embryonic-appearing thymus and persistent production of alpha-fetoprotein—features suggesting a generalized disorder of tissue differentiation.
German noun plural reconsidered
Authors: Dieter Wunderlich
Journal: Behavioral and Brain Sciences (1999)

German noun plurals not ending in -s are not as irregular as Clahsen suggests. Feminine nouns get the -n plural, unless they umlaut and are subject to a constraint that requires a reduced final syllable in the plural. Another regular class is masculine nouns ending in schwa, which are weakly inflected. It is suggested that more differentiated psycholinguistic experiments can identify these regularities.
A Duty to Participate in Research: Does Social Context Matter?
Authors: Inmaculada de Melo-Martín
Journal: The American Journal of Bioethics (2008)

Because of the important benefits that biomedical research offers to humans, some have argued that people have a general moral obligation to participate in research. Although the defense of such a putative moral duty has raised controversy, few scholars, on either side of the debate, have attended to the social context in which research takes place and where such an obligation will be discharged. By reflecting on the social context in which a presumed duty to participate in research will obtain, this article shows that decontextualized discussions of this putative moral obligation are problematic.