tbuckley/cabot-search huggingface dataset:
Molecular Rules Governing <i>De Novo</i> Methylation in Cancer
Authors: Deborah Nejman, Ravid Straussman, Israel Steinfeld, Michael Ruvolo, Douglas Roberts, Zohar Yakhini, Howard Cedar
Journal: Cancer Research (2014)

Abstract De novo methylation of CpG islands is seen in many cancers, but the general rules governing this process are not known. By analyzing DNA from tumors, as well as normal tissues, and by utilizing a range of published data, we have identified a universal set of tumor targets, each with its own “coefficient” of methylation that is largely correlated with its inherent relative ability to recruit polycomb. This pattern is initially formed by a slow process of de novo methylation that occurs during aging and then undergoes expansion early in tumorigenesis, where we hypothesize that it may act as an inhibitor of development-associated gene activation. Cancer Res; 74(5); 1475–83. ©2014 AACR.
Abstract IA3-2: Utilization of genomic signatures to guide therapeutic decisions
Authors: Joseph R. Nevins
Journal: Clinical Cancer Research (2010)

Abstract The heterogeneity of human cancers presents major challenges in understanding disease mechanisms as well as in developing an effective therapeutic strategy for the individual patient. The ability to tailor cancer therapy to characteristics of the individual patient, both with a focus on better utilization of existing standard-of-care regimens as well as new investigational drugs. Towards these goals, we have developed gene expression signatures that have the capacity to predict sensitivity to cytotoxic chemotherapeutics, and utilized these in prospective trials to determine their capacity to guide choice amongst multiple options. In addition, we have also made use of expression profiling to develop signatures of oncogenic pathway deregulation that can then be used to profile the state of these pathways within populations of tumors. These pathway signatures have been useful in dissecting disease heterogeneity, identifying subgroups of tumors with again distinct outcomes, and providing a link in pathway activation with therapeutics. We have extended this concept to develop more refined signatures that can dissect the complexities of many of the known signaling pathways, providing a more precise capacity to probe the activity or deregulation of the pathway and linking to a broader array of therapeutics. This approach, when combined with the capacity to predict chemotherapy use, has the potential to identify therapeutic strategies that make use of all available drugs, matched to the characteristics of the individual patient and thus an approach towards the development of personalized treatment options for the individual patient. Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-2.
The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model
Authors: Weiguo Hu, Richard Jin, Jinyan Zhang, Tao You, Zhihai Peng, Xiaowen Ge, Roderick T. Bronson, Jose A. Halperin, Joseph Loscalzo, Xuebin Qin
Journal: Blood (2010)

Abstract Pulmonary arterial hypertension (PAH) is suspected to be a strong mortality determinant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimentally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, intermedilysin (ILY), exclusively lyses the erythrocytes of transgenically expressing human CD59 mice (ThCD59RBC), thereby inducing ILY-dose–dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailability and massive platelet activation/aggregation leading to the formation of massive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Therapeutic interventions enhancing NO bioactivity or inhibiting platelet activation prevented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pressure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and prevention of hemolysis-associated (fatal) PAH.
Home dialysis: the competition between CAPD and hemodialysis
Authors: Roger S. Johnson
Journal: JAMA (1981)

Hemodialysis carried out in special facilities is, if not threatened, at least slipping a bit from its position as the dominant mode of therapy for patients with end-stage renal disease. The most remarkable single change, occurring within the last three years, has been the increased number of patients using continuous ambulatory peritoneal dialysis (CAPD). At the recent Controversies in 1981 Nephrology meeting held in Arlington, Va, participants debated the safety and efficacy of CAPD with respect to various patient groups. There were strong warnings that economic and political factors will favor home dialysis in the future, but within that context, some nephrologists are still unconvinced that CAPD is as safe and effective as hemodialysis. Since hemodialysis was brought under Medicare coverage by federal legislation in 1972, the impact on nephrology has been tremendous. Administered by the Health Care Financing Administration (HCFA), Medicare's End-Stage Renal Disease Program has paid 80% of
Approval of Zidovudine (AZT) for Acquired Immunodeficiency Syndrome
Authors: Itzhak Brook
Journal: JAMA (1987)

THE ANTI-INFECTIVE Advisory Committee to the Food and Drug Administration (FDA) recently recommended the approval of zidovudine (azidothymidine [AZT]) for use as a treatment of selected patients with acquired immunodeficiency syndrome (AIDS), but only for those with advanced illness characterized by<i>Pneumocystis carinii</i>pneumonia and depressed immunity and for symptomatic cases of AIDS-related complex (ARC). It did not, however, recommend approval of zidovudine for treatment of pre-AIDS or nonadvanced AIDS cases with other opportunistic infections. Within two months of that recommendation, the FDA released the drug for use for the above indications. The committee, which I chaired, was made up of 11 medical experts in infectious diseases and other disciplines; it was asked to review data from one placebo-controlled clinical trial of patients with AIDS who had recovered from their first episode of<i>P carinii</i>pneumonia before enrollment and patients with ARC who had multiple clinical symptoms, such as oral
<i>Borrelia miyamotoi:</i>More Lessons on Disease Discovery
Authors: Durland Fish
Journal: Annals of Internal Medicine (2013)

Letters5 November 2013Borrelia miyamotoi: More Lessons on Disease DiscoveryDurland Fish, PhDDurland Fish, PhDFrom Yale School of Public Health, New Haven, Connecticut.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-159-9-201311050-00018 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I read Branda and Rosenberg's (1) editorial with great interest. Readers may be interested to know that my colleagues and I discovered Borrelia miyamotoi in Ixodes scapularis ticks more than 10 years ago and were able to show transmission by infected ticks to mice with subsequent antibody response and persistent infection (2). We also showed that this organism was widespread in I. scapularis, with a mean prevalence of about 2%. We then applied 5 unsuccessful times to the National Institutes of Health and the Centers for Disease Control and Prevention for funding to determine whether this organism ...References1. Branda JA and Rosenberg ES. Borrelia miyamotoi: a lesson in disease discovery [Editorial]. Ann Intern Med. 2013;159:61-2 LinkGoogle Scholar2. Scoles GA, Papero M, Beati L, and Fish D. A relapsing fever group spirochete transmitted by Ixodes scapularis ticks. Vector Borne Zoonotic Dis. 2001;1:21-34. [PMID: 12653133] CrossrefMedlineGoogle Scholar3. Platonov AE, Karan LS, Kolyasnikova NM, Makhneva , Toporkova MG, Maleev VV, et al. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011;17:1816-23. [PMID: 22000350] CrossrefMedlineGoogle Scholar4. Schwartz I, Fish D, and Daniels TJ. Prevalence of the rickettsial agent of human granulocytic ehrlichiosis in ticks from a hyperendemic focus of Lyme disease [Letter]. N Engl J Med. 1997;337:49-50. [PMID: 9213773] CrossrefMedlineGoogle Scholar5. Anderson JF and Armstrong PM. Prevalence and genetic characterization of Powassan virus strains infecting Ixodes scapularis in Connecticut. Am J Trop Med Hyg. 2012;87:754-9. [PMID: 22890037] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAuthors: Durland Fish, PhDAffiliations: From Yale School of Public Health, New Haven, Connecticut.Disclosures: Grant: Mathers Charitable Foundation, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, Gordon & Llura Gund Foundation. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoBorrelia miyamotoi: A Lesson in Disease Discovery John A. Branda and Eric S. Rosenberg Metrics 5 November 2013Volume 159, Issue 9 Page: 648 Keywords Antibody production Encephalitis Genetics Human granulocytic anaplasmosis Lyme disease Reasoning Ticks Zoonoses ePublished: 5 November 2013 Issue Published: 5 November 2013 Copyright & PermissionsCopyright © 2013 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Treatment of Very Early Rheumatoid Arthritis With Symptomatic Therapy, Disease-Modifying Antirheumatic Drugs, or Biologic Agents
Authors: Axel Finckh, Nick Bansback, Carlo A. Marra, Aslam H. Anis, Kaleb Michaud, Stanley Lubin, Marc White, Sonia Sizto, Matthew H. Liang
Journal: Annals of Internal Medicine (2009)

Background: Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. Objective: To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. Design: Decision analytic model with probabilistic sensitivity analyses. Data Sources: Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. Target Population: U.S. adults with very early RA (symptom duration ≤3 months). Time Horizon: Lifetime. Perspective: Health care provider and societal. Intervention: 3 management strategies were compared: a symptomatic or "pyramid" strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate. Outcome Measures: Cost per quality-adjusted life-year (QALY) gained. Results of Base-Case Analysis: By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater. Results of Sensitivity Analysis: The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed. Limitations: Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics. Conclusion: According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.
Dissolving unwanted submental fat
Authors: N.J. Lowe
Journal: British Journal of Dermatology (2014)

Journal Article Dissolving unwanted submental fat Get access N.J. Lowe N.J. Lowe Cranley Clinic 3 Harcourt House 19a Cavendish Square London U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 2, 1 February 2014, Pages 237–238, https://doi.org/10.1111/bjd.12762 Published: 01 February 2014
Replication of Prostate Cancer Risk Loci in a Japanese Case–Control Association Study
Authors: Hiroki Yamada, Kathryn L. Penney, Hiroyuki Takahashi, Takahiko Katoh, Yuko Yamano, Minoru Yamakado, Takahiro Kimura, Hidetoshi Kuruma, Yuko Kamata, Shin Egawa, Matthew L. Freedman
Journal: JNCI Journal of the National Cancer Institute (2009)

Two prostate cancer genome-wide scans in populations of European ancestry identified several genetic variants that are strongly associated with prostate cancer risk. The effect of these risk variants and their cumulative effect in other populations are unknown.We evaluated the association of 23 risk single-nucleotide polymorphisms (SNPs) with prostate cancer risk and clinical covariates (Gleason score, tumor aggressiveness, and age at diagnosis) in men of Japanese ancestry (311 case subjects and 1035 control subjects) using unconditional logistic regression. We also used logistic regression to test the association between increasing numbers of independently associated risk alleles and the risk of prostate cancer, prostate cancer aggressiveness, and age at diagnosis. All statistical tests were two-sided.Seven of the 23 SNPs (five independent loci) were associated with prostate cancer risk (P values ranged from .0084 to 2.3 x 10(-8) and effect sizes [estimated as odds ratios, ORs] ranged from 1.35 to 1.82). None of the seven SNPs was associated with Gleason score or aggressive disease. rs6983561 and rs4430796 were associated with age at diagnosis (Ps = .0188 and .0339, respectively). Men with six or more risk alleles (27% of case patients and 11% of control subjects) had a higher risk of prostate cancer than men with two or fewer risk alleles (7% of case patients and 20% of control subjects) (OR = 6.22, P = 1.5 x 10(-12)).These results highlight the critical importance of considering ancestry in understanding how risk alleles influence disease and suggest that risk estimates and variants differ across populations. It is important to perform studies in multiple ancestral populations so that the composite genetic architecture of prostate cancer can be rigorously addressed.
Activation of antigen-specific suppressor T cells in the presence of cyclosporin requires interactions between T cells of inducer and suppressor lineage.
Authors: N Mohagheghpour, C J Benike, G Kansas, C Bieber, E G Engleman
Journal: Journal of Clinical Investigation (1983)

To probe the mechanism of suppressor T cell generation in man, we have carried out mixed leukocyte reactions (MLR) in the presence of cyclosporin (CsA), a fungal metabolite which prevents the generation of cytotoxic lymphocytes while permitting activation of suppressor cells. After a 12-d MLR in the presence of 1 microgram/ml CsA, T cells were fractionated into subsets with monoclonal antibodies, and each subset was tested for the ability to inhibit a second fresh MLR that is devoid of CsA. The results show that Leu 2+ T cells derived from the first culture suppress the second MLR in an HLA-DR antigen-specific manner and in the absence of detectable lysis of stimulator cells. However, Leu 2+ cells do not develop into suppressor cells unless acted upon by alloantigen-primed Leu 3+ inducer cells. Furthermore, only those Leu 3+ cells that also express the Leu 8 marker (Leu 3+, 8+) are capable of inducing suppressor cells. Thus, antigen-specific feedback inhibition of an immune response in man results from an ordered series of interactions between T cells of distinct phenotype.
Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse
Authors: G A Clarke
Journal: Gut (2003)

<b>Background and aims:</b> Newly synthesised cholesterol contributes poorly to biliary lipid secretion but may assume greater importance when the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) is upregulated. As this occurs in the gall stone susceptible C57L/J inbred mouse, we employed two cholesterol biosynthesis inhibitors, Tu 2208 and Ro 48-8071, potent inhibitors of squalene epoxidase and oxidosqualene-lanosterol cyclase, respectively, to assess their potential in preventing cholesterol cholelithiasis in the C57L/J mouse strain. Mice were fed a lithogenic diet comprising a balanced nutrient intake with 15% dairy fat, 1% cholesterol, and 0.5% cholic acid added. <b>Methods:</b> We determined gall stone phenotype, HMGR activity, biliary lipid secretion rates, and counterregulatory events in male C57L/J mice and gall stone resistant AKR treated with Tu 2208 (30–60 mg/kg/day) or Ro 48-8071 (30–100 mg/kg/day), while ingesting chow or the lithogenic diet. <b>Results:</b> Both agents reduced the gall stone prevalence rate from 73% to 17% in C57L/J mice, inhibited HMGR activity, and decreased hepatic cholesterol concentrations without appreciably influencing biliary cholesterol secretion. In C57L as well as AKR mice, both agents increased biliary phospholipid (which is mostly phosphatidylcholine) secretion rates and at the highest doses effectively reduced the biliary cholesterol saturation index. <b>Conclusions:</b> Cholesterol biosynthesis inhibitors acting distally to squalene do not reduce biliary cholesterol secretion rates despite reductions in cholesterol biosynthesis and hepatocellular levels. However, they effectively prevent gall stone formation through stimulation of pathways that lead to enhanced biliary phospholipid secretion.
Physical treatments have valuable role in osteoarthritis
Authors: Jan M Bjordal, Rodrigo Alvaro Brandao Lopes-Martins, Bård Bogen, Mark Johnson
Journal: BMJ (2006)

EDITOR—Hunter and Felson deliver a consistent and seemingly thorough clinical review about managing knee osteoarthritis for primary care doctors.1 We commend them for promoting the role of non-pharmacological interventions and for highlighting the problem of inadequate funding because of “lucrative opportunities for drug development.” However, one striking omission in their review …
&lt;emph type="ital"&gt;JAMA&lt;/emph&gt; Classics: Celebrating 125 Years of Publication
Authors: Catherine D. DeAngelis
Journal: JAMA (2008)

THIS ISSUE MARKS THE 125TH ANNIVERSARY OR quasquicentennial (we dare you to say that 3 times without getting tongue-tied) of JAMA, which began publication in 1883. In that year, Chester A. Arthur was the US president and the first telephone line connected New York and Chicago. In the 1883 world of biology and medicine, Robert Koch discovered the cholera bacillus and Georgios N. Papanikolaou, pioneer in cervical cytology, was born. The first issue of JAMA, published on July 14, 1883 (FIGURE), included a wide range of articles that apparently were selected to be of interest to a general medical readership. These reports covered a wide range of topics, including tobacco smoking in children, blunt chest trauma, and neurological disorders. Other articles in that issue described therapeutic interventions, such as treatment of otorrhea and diabetes and surgical techniques. All of this information was available for 10 cents per issue ($5 for an annual subscription), with costs probably at least partially defrayed with advertisements (mostly for schools and books, but also for medicinal products) that also appeared in that issue. Some things change little over time. Over the past 125 years, JAMA has published many important groundbreaking and practice-changing articles, some of which we now refer to as JAMA Classics. To celebrate our quasquicentennial, over the next year we will republish 24 of those classic articles online accompanied in print by a JAMA Classics Commentary that provides a brief summary of the original article and an update of the topic covered in the classic article. Whenever possible the Commentary will be written by individuals from the same institution as the authors of the classic article. To start this series, with this issue of JAMA we are publishing online the full text of the classic article “The Surgical Treatment of Malformations of the Heart in Which There Is Pulmonary Stenosis or Pulmonary Atresia” authored by Alfred Blalock, MD, and Helen B. Taussig, MD. The accompanying Commentary in this issue of JAMA is authored by Anne Murphy, MD, and Duke Cameron, MD; all 4 authors are from Johns Hopkins University School of Medicine. Both women were/are pediatric cardiologists and both men were/are pediatric surgeons. One difference is that, unlike the original article, the Commentary has the woman as first author. We hope you will enjoy the JAMA Classics series as much as we have in choosing the articles and collaborating with the authors of the Commentaries. Read, learn, and enjoy.
Alcoholics and liver transplantation. The Ethics and Social Impact Committee of the Transplant and Health Policy Center
Authors: C. Cohen
Journal: JAMA (1991)

Two arguments underlie a widespread unwillingness to consider patients with alcoholic cirrhosis of the liver as candidates for transplantation. First, alcoholics are morally blameworthy, their condition the result of their own misconduct; such blameworthiness disqualifies alcoholics in unavoidable competition for organs with others who are equally sick but blameless. Second, because of their habits, alcoholics will not exhibit satisfactory rates of survival after transplantation; good stewardship of a scarce lifesaving resource therefore requires that alcoholics not be considered for liver transplantation. These arguments are carefully analyzed and shown to be defective. There is not good moral or medical reason for categorically precluding alcoholics as candidates for liver transplantation. It would, in addition, be unjust to implement such a preclusion simply because others might respond negatively if we do not.There is widespread unwillingness to consider patients with alcoholic cirrhosis for liver transplantation. Cohen and Benjamin examine the two arguments that underlie the exclusion of alcoholics from a potentially life-saving procedure. The first, a moral argument, holds that alcoholics are to blame for their condition, and that this blame excludes them from competition for scarce donor livers with other patients with end-stage liver disease who are not to blame for their illness. The second argument, taken from a medical perspective, holds that alcoholics do not do well after liver transplantation, and that scarce donor livers should not be allocated to a group with a poor survival rate. Cohen and Benjamin reject as unfair and unacceptable both arguments for withholding liver transplantation from alcoholics. They also reject the argument that public support for transplantation will suffer if it becomes known that donated organs are going to alcoholics.