tbuckley/cabot-search huggingface dataset:
352. Intentional Killing of Normal Melanocytes by Gene Transfer Generates Curative Anti Melanoma Immunity without Obligate Autoimmunity
Authors: Gregory Daniels, Luis Sanchez-Perez, Timothy Kottke, Rosa M. Diaz, Jill Thompson, Mayoi Lai, Michael Gough, Mahzuz Karim, Andrew Bushell, Heung Chong, Alan Melcher, Kevin Harrington, Richard G. Vile
Journal: Molecular Therapy (2004)

Most tumor vaccination strategies depend upon the molecular identification of specific tumor rejection antigens and/or the use of patient derived tumor materials. In addition, there is a strong correlation between the use of cancer vaccines and the induction of autoimmune reactivity. We hypothesised that in situ, inflammatory killing of a normal tissue from which a tumor derives may generate autoimmune reactivity to self antigens expressed in that tissue as well as in the tumor cells. Here we report that simple intradermal injection of 2 plasmids promoted tissue specific, inflammatory killing of melanocytes and induced an immune response that eradicated systemically established B16 tumors. The therapeutic response was CD8+T cell dependent but, significantly, was rapidly suppressed in vivo and did not induce autoimmune disease in animals in which tumors had been cured. The T cell response was characterized by selection of B16 tumor variants which grow extremely aggressively in vivo, are amelanotic and which have lost expression of the tyrosinase and TRP-2 antigens. The mechanism of antigen loss was, at least in part, through epigenetic mechanisms. These could be reversed by long term growth in culture or, more rapidly, by treatment with the de-methylating agent 5-azacytidine. Depletion of putative regulatory T cells within the CD25+ T cell population improved therapeutic efficacy. Finally, vaccination could be further improved using adoptive transfer of activated T cells with specificity for an antigen that was not a target of the initial T cell response raised by melanocyte killing. These data demonstrate that inflammatory killing of a normal tissue can lead to the immunoselection of tumor cell growth variants. They also raise the prospect that such vaccinations could be effectively used in combination with other conventional anti tumor treatment modalities.
Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5-FU) in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R&amp;M SCCHN) (EXTREME)
Authors: J. B. Vermorken, R. Mesia, M. E. Vega-Villegas, E. Remenar, R. Hitt, A. Kawecki, S. Rottey, D. Zabolotnyy, J. Erfan, N. Amellal
Journal: Journal of Clinical Oncology (2006)

5537 Background: The epidermal growth factor receptor (EGFR) is expressed in nearly all SCCHN and carries a strong prognostic significance, providing the rationale for using EGFR-targeted agents, such as cetuximab, in this indication. This study assesses the efficacy and safety of cetuximab in combination with chemotherapy commonly used in the treatment of R&amp;M SCCHN. Methods: Patients (pts) were enrolled into this phase III trial from December 2004 to December 2005 and randomized either to Group A: cetuximab (first dose 400 mg/m 2 then 250 mg/m 2 weekly) plus a maximum of 6 three-weekly cycles of cisplatin (100 mg/m 2 IV on day 1) or carboplatin (AUC 5, day 1) and 5-FU (1000 mg/m 2 /day continuous infusion for the first 4 days of each cycle) or to Group B: cisplatin or carboplatin with 5-FU as before. Cetuximab was administered until progression or unacceptable toxicity. Primary endpoint is overall survival time; secondary endpoints are progression-free-survival, response rate, disease control rate, safety, and Quality of Life. It was planned to randomize a total number of 420 pts in order to detect a difference in improvement in overall survival of 2.5 months. Results: At the end of the recruitment,440 pts have been randomized, to date 320 pts are under treatment, 21 have withdrawn from the study and 99 have completed the study. The Data Safety Monitoring Board (DSMB) has performed an independent preplanned safety analysis from the first 140 pts, 138 pts of whom were treated. Patients were followed for a minimum of 6 weeks: M/F122/16, median age57 years [range, 38–79],median Karnofsky performance status (KPS) 80 [range, 70–100]. In this safety analysis, there were 14 deaths, none of which were treatment related. The most frequent drug related grade 3–4 toxicity was mainly represented by neutropenia, thrombocytopenia and anemia. Conclusions: The DSMB evaluated baseline and safety data, found no reason to stop the trial and recommended continuation of the study. [Table: see text]
Nosocomial Influenza B Virus Infection in the Elderly
Authors: LEE P. VAN VORIS
Journal: Annals of Internal Medicine (1982)

A hospital-acquired outbreak of influenza-like illness that involved 29 patients during 4 weeks was detected in March 1980. The average age of the patients was 63 years. Eighteen of the 29 patients with symptoms had influenza B virus infection documented by virus isolation, fourfold or greater hemagglutination inhibition antibody increases, or both. The attack rate among all hospitalized inpatients was 20%. Absenteeism of the hospital staff because of influenza-like illnesses preceded the outbreak by several weeks, suggesting staff-to-patient transmission. The patients' sera during acute illness had low hemagglutination inhibition antibody titers (geometric mean titer of 1:21) against contemporary influenza B virus antigens, indicating that the patients were highly susceptible to influenza B virus. Only one patient had received trivalent influenza vaccine during the preceding year. The excess hospital cost resulting from the outbreak was $13 270 or $458 per patient. Our observations show that the elderly are at risk of developing nosocomial influenza B virus infection and that these illnesses are costly. Continued efforts to develop efficient influenza immunization programs for elderly persons and hospital staff are worthwhile.
Early elimination of drug candidates with potentially adverse side effects in a rat liver toxicity study using a novel, quantitative multiplex gene expression assay
Authors: Yong Wu, Kathryn Sciabica, Kahuku Oades, Gordon Vansant, Jane Luo
Journal: Clinical Cancer Research (2008)

B30   Gene expression analysis offers valuable insight regarding the possible side effects of candidate drugs, leading to the selection of therapies that have fewer side effects. Expression profiles from small gene sets (5-30 genes) can be highly effective in prescreening a large number of compounds in cell culture. This study examines the use of a novel, multiplex-gene-expression assay that measures the variation in cellular transcription profiles as indicators of different toxicity mechanisms or pathways. The assay is capable of measuring very small changes in expression with precision that is below the noise of most other assays. The multiplex contains 23 genes involved in toxicity, stress, DNA damage and apoptosis along with 3 reference genes. Gene expression profiles of rat primary hepatocytes or C9 cells, treated with chemical compounds at different doses, were compared to the expression profiles of control cells. A subset of genes; which included Nqo1, Gadd45, Gadd153, p21 and Ho1; were upregulated in the presence of troglitazone; while CyclinD1 was downregulated relative to the control. The Cyp1 gene family was differentially expressed in response to increasing doses of benzo[a]pyrene. These results demonstrate the capability of this multiplex assay to detect differences in levels of gene expression between treated and untreated cells. Further, the effects of increasing doses of particular compounds can be quantified. This leads to a rapid evaluation of compounds and early elimination of chemicals with adverse effects, which could reduce the number of costly animal experiments. Our results demonstrate that multiplex gene expression profiling is a powerful tool that can expedite investigations of drug toxicity and cellular response in a cost-effective manner.  Note: For research use only; not for use in diagnostic procedures.
Therapeutic options for erythropoietic protoporphyria
Authors: D.J. Todd
Journal: British Journal of Dermatology (2000)

Journal Article Therapeutic options for erythropoietic protoporphyria Get access D.J. Todd D.J. Todd Department of Dermatology, Faculty of Medicine, Jordan University of Science & Technology, Irbid, PO Box 3030, Jordan E‐mail: djtodd@go.com.jo Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 4, 1 April 2000, Page 826, https://doi.org/10.1046/j.1365-2133.2000.03442.x Published: 01 April 2000
Abstract 1424: Taxus but not Cypher Drug Eluting Stents induce Endothelial Dysfunction in the Distal Coronary Microvasculature
Authors: Oana Sorop, Wendy W Batenburg, Sietse-Jan Koopmans, Ruud Dekker, Dirk J Duncker, A. H Danser, Heleen M van Beusekom, Wim J van der Giessen
Journal: Circulation (2007)
Report Cites Shortcomings in Quality of Pediatric Health Care
Authors: Mike Mitka
Journal: JAMA (2004)

cartilage, he explained. “Full development of these capabilities would permit us to monitor emerging therapeutic protocols in humans using MRI,” he said. “It would permit us to assess how well the healing process is progressing, and potentially let us make real-time adjustments in the therapy in order to improve that process.” Spencer’s team carries out MRI studies with 3-dimensional engineered cartilage grown in a hollow-fiber bioreactor. “This system allows for the growth of large, millimeters-thick pieces of cartilage tissue starting from just chondrocytes,” said Spencer. “We’re looking at the effects of a variety of growth conditions, growth modulators, therapeutic agents, and other stimuli on cartilage development.” Ongoing experiments indicate, for example, that ibuprofen has catabolic effects on growing cartilage, results that are consistent with cell culture data from the 1980s, said Spencer. These findings raise the question of whether nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided after procedures in which growthofnewcartilage isdesired, including autologous chondrocyte implantation, microfracture, or scaffold implantation. His group is continuing to look into the effects of other NSAIDs, as well as less traditional therapeutic agents such as glucosamine. Researchers predict that progress in understanding osteoarthritis and developing new ways to produce healthy cartilage and bone will eventually pay off in theclinic. “Rather thanessentially just watching while so many of our patients become progressively disabled, we now have some realistic hope of being able to fight this disease,” said Spencer.
Paediatric pathology service close to collapse
Authors: Zosia Kmietowicz
Journal: BMJ (2001)

Women who miscarry or lose a baby shortly after birth but are refusing to allow a postmortem examination to be carried out are missing out on vital information that could help them to have a healthy baby, doctors have warned.

Public confidence in paediatric pathology has plummeted in the aftermath of the retained organ affair at Alder Hey Children's Hospital in Liverpool, with the specialty now close to collapse. An exodus of experienced doctors has left services seriously understaffed, and, unless the public can be reassured of the value of perinatal postmortem examinations, many families will never know why their baby died …
Emergency psychiatric assessment of violence
Authors: J C Beck, K A White, B Gage
Journal: American Journal of Psychiatry (1991)

The purpose of the study was to 1) ascertain whether there are clinical and demographic characteristics that distinguish dangerous from nondangerous patients evaluated in a psychiatric emergency service and 2) identify variables that distinguish dangerous patients who are hospitalized form those who are not.The authors conducted a case comparison study of 99 psychiatric emergency patients whom staff identified as dangerous to others, that is, violent or potentially violent. Clinical staff were interviewed and records reviewed. These data were contrasted with record review data for 95 nondangerous patients.Log linear analysis showed that 1) variables relating to violence in community samples--age, sex, and past history of violence--related minimally or not at all to violence in this sample and 2) disposition to hospital versus community was associated with psychotic mental status and restraint in the psychiatric emergency service. Patients requiring restraint were more likely to have recently committed assault or battery and to have been brought in by the police.Enduring personal characteristics of patients relate neither to psychiatric emergency service assessments of current dangerousness nor to the decision to hospitalize. These determinations appear to be related to assessments of current patient state and immediate past behavior.
ABC of learning and teaching in medicine: Skill based assessment
Authors: S. Smee
Journal: BMJ (2003)

Skill based assessments are designed to measure the knowledge, skills, and judgment required for competency in a given domain. Assessment of clinical skills has formed a key part of medical education for hundreds of years. However, the basic requirements for reliability and validity have not always been achieved in traditional “long case” and “short case” assessments. Skill based assessments have to contend with case specificity, which is the variance in performance that occurs over different cases or problems. In other words, case specificity means that performance with one patient related problem does not reliably predict performance with subsequent problems.

For a reliable measure of clinical skills, performance has to be sampled across a range of patient problems. This is the basic principle underlying the development of objective structured clinical examinations (OSCEs). Several other structured clinical examinations have been developed in recent years, including modified OSCEs—such as the Royal College of Physicians' Practical Assessment of Clinical Examination Skills (PACES) and the objective structured long case (OSLER). This article focuses mainly on OSCEs to illustrate the principles of skill based assessment.

The objective structured clinical examination (OSCE) was introduced over 30 years ago as a reliable approach to assessing basic clinical skills. It is a flexible test format based on a circuit of patient based “stations.”

At each station, trainees interact with a patient or a “standardised patient” to demonstrate specified skills. Standardised patients are lay people trained to present patient problems realistically. The validity of interactions with real patients, however, may be higher than that with standardised patients, but standardised patients are particularly valuable when communication skills are being tested.

OSCE stations may be short (for eample, five minutes) …
Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome
Authors: Sander M. Houten, Wietse Kuis, Marinus Duran, Tom J. de Koning, Annet van Royen-Kerkhof, Gerrit J. Romeijn, Joost Frenkel, Lambertus Dorland, Martina M.J. de Barse, Wim A.R. Huijbers, Ger T. Rijkers, Hans R. Waterham, Ronald J.A. Wanders, Bwee Tien Poll-The
Journal: Nature Genetics (1999)
Studies of arteriosclerosis in japanese and american men
Authors: William Insull, P. Dieter Lang, Bartholomew P. Hsi, Saburo Yoshimura
Journal: Journal of Clinical Investigation (1969)

The proportions of fatty acids in lipids of subcutaneous adipose tissue was compared in closely age-matched, urban men from two populations with a great difference in mortality from arteriosclerosis, namely in 50 Americans and 56 Japanese aged 15-65 yr who had died suddenly and unexpectedly. Specimens from both groups were analyzed side by side for fatty acids by gas-liquid chromatography. Compared with Japanese, Americans had significantly (P<0.01) higher proportions of lauric (+ 0.2%), myristic (+ 0.4%), palmitic (+ 1.4%), stearic (+ 2.2%), and oleic (+ 5.3%) and lesser of palmitoleic (- 1.8%), linoleic (-6.3%), and linolenic (-0.4%) acids. Japanese had higher proportions of longer chain polyunsaturated fatty acids. The distributions of fatty acids for the groups at ages 35-44 yr had significant differences. With age, Americans showed significant increases of palmitic and oleic acids and decreases of lauric, myristic, stearic, and linoleic acids; Japanese showed no correlations of proportions of fatty acids with age. The significant correlations between per cent standard body weight and fatty acids in Americans were positive for palmitic and negative for lauric and stearic acids, and in Japanese, negative for myristic acid. The patterns of interacid correlations were dissimilar for the groups. These patterns may be stable characteristics of these groups providing further insight into their fatty acid metabolism. The relationships with the fatty acid compositions of the American and Japanese diets are discussed.
Voprosi Onkologii (Problems of Oncology) N. N. Petrov, A. I. Rakov, A. I. Serebrov, S. A. Kholdin, and L. M. Shabad (eds.). In Russian. Moscow: Acad. Meditsinskikh Nauk SSSR, 1950. Pp. 536. Price: 37 roubles, 80 kopeks.
Authors: Michael B. Shimkin
Journal: Cancer Research (1953)
A PRELIMINARY NOTE ON AN INTERESTING EXPERIMENT
Authors: Reginald Fitz
Journal: Annals of Internal Medicine (1947)

Editorial1 November 1947A PRELIMINARY NOTE ON AN INTERESTING EXPERIMENTREGINALD FITZ, M.D., F.A.C.P.REGINALD FITZ, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-27-5-835 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptOn April 15, 1934, as an aid to the promotion of clinical research in this country, the Board of Regents established the "Research Fellowship of the American College of Physicians." This fellowship, on recommendation of the Committee on Fellowships and Awards, was given each year from 1934 to 1943—when war interrupted the program—to a varying number of suitably promising candidates, no single one ever holding it for more than a period of 12 months.The Committee on Fellowships and Awards, first called the Committee on the John Phillips Memorial Prize, was established in 1929 as a committee of five with... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *Chairman, Committee on Fellowships and Awards, 1947. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 November 1947Volume 27, Issue 5Page: 835-840KeywordsFellowships ePublished: 1 December 2008 Issue Published: 1 November 1947 PDF downloadLoading ...
Abstract B29: Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations
Authors: Grazia Ambrosini
Journal: Cancer Research (2015)

Abstract Uveal melanoma (UM) represents the most common intraocular malignancy, and there are no effective treatments for this aggressive disease. Nearly 80% of UM is characterized by oncogenic mutations in G protein subunits Gnaq and Gna11, and 70% have extra copies of the oncogene MYC. Chromatin regulators have become attractive targets for cancer therapy. In particular, the BET-bromodomain inhibitor JQ1 has shown selective inhibition of c-Myc expression, followed by the suppression of c-Myc-dependent target genes. Treatments of UM cell lines with JQ1 showed that the Gnaq/Gna11 mutant cells were the most sensitive to BET inhibition with induction of cell death, while the cells without the mutations underwent cell cycle arrest in G1. Microarray analysis of UM cells revealed that several genes were differentially regulated by JQ1 treatment in Gnaq/11 mutant cells, with the downregulation of c-Myc, of the anti-apoptotic protein Bcl-2, and DNA repair proteins Rad51 and Brca1. While depletion of each of these genes did not affect cell viability, the concomitant silencing of Rad51 and Bcl-2 represented the minimal requirement to mimic the apoptotic effects of JQ1. As opposed to hematopoietic cancer cell lines, c-Myc depletion did not seem to play a major role in inhibiting the growth of these cells. Furthermore, the treatment with JQ1 resulted in significant antitumor activity in a mouse xenograft model of uveal melanoma with Gnaq mutation. Our results suggest the potential therapeutic use of BET bromodomain inhibitors for treating uveal melanoma with Gnaq/Gna11 mutations. Citation Format: Grazia Ambrosini. Differential effects of BRD4 inhibition on uveal melanoma cells with Gnaq/11 mutations. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B29.
Abstract 20074: Hemodynamic Profile of Prolonged Normothermic, Mild Hypothermic, and Deep Hypothermic Emergency Cardiopulmonary Bypass Reperfusion in Rats
Authors: Ingrid A Magnet, Florian Ettl, Andreas Schober, Alexandra-Maria Warenits, Christoph Testori, Daniel Grassmann, Michael Wagner, Christian Clodi, Christoph Schriefl, Ursula Teubenbacher, Sandra Högler, Wolfgang Weihs, Fritz Sterz, Andreas Janata
Journal: Circulation (2014)

Background: The hemodynamic profile of rats randomized into prolonged normothermic (NT, 37±0.5°C), mild hypothermic (MH, 33±0.5°C) or deep hypothermic (DH, 27±0.5°C) reperfusion with emergency cardiopulmonary bypass (ECPB), following refractory ventricular fibrillation cardiac arrest (VF CA) was explored. Methods: Fifty adult male Sprague-Dawley rats were put on bypass for 15 min, following 10 min of VF CA. The ECPB setup included a circulating water bath which temperature controlled all animals at target. After 15 min, rats were defibrillated, weaned from bypass, and controlled at 33°C (MH, DH) or 37°C (NT) externally. All rats received a single dose of epinephrine (30 μg/kg), heparin and sodium bicarbonate with the crystalloid priming of the ECPB circuit. ECPB flow rate was kept at 100 mL/kg in all groups. Mean arterial pressure (MAP) was continuously monitored in the femoral artery and is presented as median with 25th/75th quartile mmHg. Results: See figure. There was no difference in MAP before or during CA. For the first 5 min of resuscitation, MAP at a given ECPB flow rate was highest in the DH group (DH 84(69;89), MH 51(49;61), NT 48(37;55) , p = &lt;.001). This was reversed during the last 5 min on bypass (DH 35(30;42), MH 44(37;64), NT 42(33;67), p = .034). For 10 min off bypass, the DH group was relatively hypotensive (DH 46(40;62, MH 64(60;77), NT 61(54;77), p = .005), which was again reversed for the remaining post resuscitation period (DH 68(60;78), MH 59(54;66), NT 53(49;62), p = .008). Conclusions: While the temperature profiles of NT and MH reperfusion were similar, DH caused initially higher pressures followed by a period of hypotension as compared to NT and MH groups at identical epinephrine doses and ECPB flow rates. Off bypass, DH animals were again relatively hypotensive, coinciding with their rewarming to mild hypothermia. Further experiments are needed to determine the cause of this, like hypothermic vasoconstriction, or altered pharmacokinetics.