tbuckley/cabot-search huggingface dataset:
B-Raf Inhibitors Induce Epithelial Differentiation in<i>BRAF</i>-Mutant Colorectal Cancer Cells
Authors: Ricarda Herr, Martin Köhler, Hana Andrlová, Florian Weinberg, Yvonne Möller, Sebastian Halbach, Lisa Lutz, Justin Mastroianni, Martin Klose, Nicola Bittermann, Silke Kowar, Robert Zeiser, Monilola A. Olayioye, Silke Lassmann, Hauke Busch, Melanie Boerries, Tilman Brummer
Journal: Cancer Research (2014)

BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf(V600E) oncoprotein. Doxycyclin-inducible knockdown of endogenous B-Raf(V600E) decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell-cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-Raf(V600E) in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells.
Necrotising fasciitis Use of skin flaps needs experience
Authors: N Mercer, H Cox
Journal: BMJ (1994)

computer illiterate" for some years yet.Computer skills should be integrated into all postgraduate courses.For example, we would add "information management including computer skills" to the content of the master's degree in general practice suggested by Lindsay F P Smith.4Students taking the master of public health at Glasgow University are now required to attain basic computer literacy.Secondly, the need for an appropriate bridge between JANET (the joint academic network, the British end of the internet) and NHS networks has been discussed in seminars as part of the "Cumberlege process."'Given the rate of growth of the internet, a well planned solution is needed urgently to prevent the growth of unofficial and uncontrolled connections.
Medicine in Defense Against Biological Warfare
Authors: David L. Huxsoll
Journal: JAMA (1989)

IT IS fitting in this issue ofThe Journalthat we turn our attention to another means of mass destruction—biological warfare. This method of warfare, first used in the sixth century BC,<sup>1</sup>is widely available, easily obtained, silent, and invisible. Whether it be a fraction of a microgram of lethal toxin inhaled by one person or a drifting cloud that can kill or incapacitate tens of thousands, the potential threat of biological warfare is clear. In this commentary, we explain why research in medical defenses against this threat is needed as we answer yes to Orient's<sup>2</sup>question, "Should medical defenses against biological warfare be researched?" We define<i>biological warfare</i>as the use of microorganisms or toxins derived from living organisms to produce death or disease in humans, animals, or plants. This definition is compatible with the National Security Decisions signed in 1969 and 1970, in which the United
Adenosine triphosphatase pontin is overexpressed in hepatocellular carcinoma and coregulated with reptin through a new posttranslational mechanism
Authors: Valérie Haurie, Ludovic Ménard, Alexandra Nicou, Christian Touriol, Philippe Metzler, Jérémy Fernandez, Danièle Taras, Patrick Lestienne, Charles Balabaud, Paulette Bioulac‐Sage, Hervé Prats, Jessica Zucman‐Rossi, Jean Rosenbaum
Journal: Hepatology (2009)

Reptin and Pontin are related ATPases associated with stoichiometric amounts in several complexes involved in chromatin remodeling, transcriptional regulation, and telomerase activity. We found that Reptin was up-regulated in hepatocellular carcinoma (HCC) and that down-regulation of Reptin led to growth arrest. We show here that Pontin messenger RNA (mRNA) is also up-regulated in human HCC 3.9-fold as compared to nontumor liver (P = 0.0004). Pontin expression was a strong independent factor of poor prognosis in a multivariate analysis. As for Reptin, depletion of Pontin in HuH7 cells with small interfering RNAs (siRNAs) led to growth arrest. Remarkably, Pontin depletion led to down-regulation of Reptin as shown with western blot, and vice versa. Whereas siRNAs induced a decrease of their cognate mRNA targets, they did not affect the transcripts of the partner protein. Translation of Pontin or Reptin was not altered when the partner protein was silenced. However, pulse-chase experiments demonstrated that newly synthesized Pontin or Reptin stability was reduced in Reptin- or Pontin-depleted cells, respectively. This phenomenon was reversed upon inhibition of proteasome or ubiquitin-activating enzyme (E1). In addition, proteasome inhibition could partly restore Pontin steady-state levels in Reptin-depleted cells, as shown by western blot. This restoration was not observed when cells were also treated with cycloheximide, thus confirming that proteasomal degradation in this setting was restricted to newly synthesized Pontin. Conclusion: Reptin and Pontin protein levels are strictly controlled by a posttranslational mechanism involving proteasomal degradation of newly synthesized proteins. These data demonstrate a tight regulatory and reciprocal interaction between Reptin and Pontin, which may in turn lead to the maintenance of their 1:1 stoichiometry. (HEPATOLOGY 2009.)
Physical Factors in the Progression of Stenotic Vascular Lesions
Authors: SIMON RODBARD
Journal: Circulation (1958)

An explanation of the progression of stenotic lesions was sought in animal experiments. After surgical decrease of the lumen of arteries, progressive ingrowth of fibrous connective tissue led to the development of stenosis with changes in the artery that resembled those of coarctation. These changes are explained by the action of local blood pressures. Phenomena such as progressive stenosis, valvulogenesis, patterns of lipid infiltration, medial hypertrophy, thinning, and cystic change are discussed in terms of the concepts derived from these studies.
Simulated blood flow and the effects on prostacyclin production in the dog femoral artery.
Authors: T Onohara, K Okadome, S Yamamura, S Mii, K Sugimachi
Journal: Circulation Research (1991)

Effects of blood flow on the production of prostacyclin (PGI2) were examined in the canine femoral artery perfused ex vivo. Each artery was perfused in situ with medium 199, under conditions of simulated blood flow. To simulate the normal and abnormal blood flow waveforms at the same mean flow rate, we developed a flow apparatus capable of making various waveforms by changing the duration when the electromagnetic valve in the circuit was open. Group I (n = 7) was exposed to a steep acceleration waveform followed by a steep deceleration, as the normal flow waveform; group II (n = 7) was exposed to a gentle sloping waveform in the deceleration phase, as the abnormal flow waveform. PGI2 was measured as 6-ketoprostaglandin F1 alpha. PGI2 production was estimated as the cumulative production for the first 5 minutes (acute response) and as the production rate after the first 30 minutes (stable production rate). Under conditions of normal flow, the acute response was 5.87 +/- 2.16 ng/cm2/5 min, whereas under conditions of abnormal flow, the rate was 2.20 +/- 0.27 ng/cm2/5 min (p less than 0.01). Stable production rates were 82.5 and 37.5 pg/cm2/min, respectively (p less than 0.05). Both the acute response and the stable production rate of PGI2 production were greater under conditions of simulated normal flow as compared with findings in the case of an abnormal flow. Our working hypothesis is that the decreased production of PGI2, as well as a deterioration in the implanted graft, under conditions of abnormal blood flow leads to a loss of late patency of the reconstructed arteries.
A COMPARATIVE STUDY BETWEEN INTRAVENOUS AND INTRACORONARY ADMINISTRATION OF HIGH DOSES ADENOSINE FOR FRACTIONAL FLOW RESERVE MEASUREMENTS, IN THE &amp;ldquo;FAME&amp;rdquo; ERA
Authors: Jose Ma Cubero, Luis S. Diaz de la Llera, Pablo Cerrato Garc&iacute;a, Manuel Villa Gil-Ortega, Javier Benezet Mazuecos, Angel Sanchez-Gonzalez
Journal: Journal of the American College of Cardiology (2012)
Expanding Dimensions of Medicine
Authors: John A. D. Cooper
Journal: JAMA (1963)

MY ASSIGNMENT in this session on "learning today for understanding tomorrow" is to explore the influence of expanding dimensions in medicine on the educational responsibilities of the liberal arts college and professional school in the preparation of the physician. It is important to note at the outset that there are many extrinsic factors which also affect the educational program for medicine. Among these are recent developments in the teaching of science, mathematics, and English in our secondary schools. Remarkable accomplishments in the high schools already are having an impact on higher education and hence on medical education. I will discuss some of these accomplishments later. It will be helpful in my discussion to divide medicine into its disciplinary and professional aspects. As Hunt has described them,<sup>1</sup>the disciplinary aspects include the body of knowledge specific to medicine and the medical sciences, the procedures involved in increasing and elaborating this
A patient's journey with myalgic encephalomyelitis
Authors: Bie Nio Ong, Daphne Evans, Andrew Bartlam
Journal: BMJ (2005)

Myalgic encephalomyelitis (ME) presents patients and their general practitioners with the challenge of managing a life shaped by chronic debilitating illness, pain, and uncertainty. The notion that body limitations resulting from illness must be recognised is shown in the literature on chronic illness, but at the same time it is necessary to understand the social context of change and diversity within which illness is conceptualised. People give meaning to their illness and altered life course with reference to socioeconomic relations, cultural perceptions and beliefs, and their interactions with health and social care services.

Myalgic encephalomyelitis represents the conundrum of uncertainty in the diagnosis, treatment, and prognosis of the disease. Many of the symptoms that people present with could be indications for other diseases, making it difficult to diagnose. Moreover, there is still some debate about the existence of the disease as a clinical category. Current guidance focuses on the symptoms of fatigue and malaise, cognitive impairment, and pain. The patient's account in this paper was collected as part of a research study on osteoarthritis of the knee. The patient, Daphne Evans, was interviewed by BNO, but the discussion centred on myalgic encephalomyelitis because she considered this condition of primary importance. Her doctor's account was added to her own account when the paper was drafted.

Daphne's story illustrates the syndrome of myalgic encephalomyelitis as a chronic and fluctuating illness with a profusion of symptoms that affect many parts of the body, which can result in severe muscle pain, physical and mental fatigue, problems with concentration and memory, and feeling unwell (box 1). Although health professionals increasingly take the patient's “life world” into account, indeterminate diseases highlight the tension between the biophysical and psychosocial aspects of illness.

#### Box 1: Daphne's journey to diagnosis

I was originally ill in 1979 and told I was very ill but nobody could …
"Audi Alteram Partem."
Authors: Chas. G. Kuhlman
Journal: JAMA (1895)

San Francisco, Cal., May 22,1895. <h3>To the Editor:</h3> —[Our esteemed correspondent, whose letter pronouncing the collective investigation of the antitoxin treatment of diphtheria impossible of execution was published in theJournalof May 11, takes exception to the summary fashion in which his first communication was treated, and furnishes the following argument, in support of his belief that the results of such investigation must be valueless.] I feel perfectly safe in saying that, in the present light of science, no living person can make a positive differential diagnosis between typical Bretannean diphtheria and allied affections—and for the following reasons: 1. A schizomycete answering (Löffler's) description has been found in less than 50 per cent. of cases of clinical diphtheria—and then never alone, always together with other forms, such as streptococci, staphylococci, pneumococci, bact.coli communis and micrococcus prodigiosus (See Hausemann, Benda, Ritter, Körte and others. Proceedings Berlin Medical Society, Nov. 28,
Respiratory impairment induced by smoking in children in secondary schools.
Authors: L Adams, D Lonsdale, M Robinson, R Rawbone, A Guz
Journal: BMJ (1984)

A longitudinal study was carried out from 1975 to 1979 in a cohort of 405 secondary school children. At yearly intervals they underwent a series of tests of pulmonary function designed to monitor lung development; some of these tests are relatively sensitive indicators of early abnormalities. A self administered questionnaire provided details of smoking habits and respiratory symptoms. The prevalence of smoking increased with age; most of those smoking at 16 had already been smoking, at least experimentally, at 13. Taking up smoking was clearly associated with the early onset of cough, production of phlegm, and shortness of breath on exertion. After two years of smoking more than a few cigarettes a day the children who smoked appeared considerably less healthy than their non-smoking peers and showed some evidence of early obstruction of the airways.
Peer-Reviewed Articles and Public Health
Authors: Enrico Girardi, Nicola Petrosillo, Maria Stella Aloisi, Lucilla Ravà, Giuseppe Ippolito
Journal: JAMA (1998)

Context.—It has been suggested that early announcements of research works to be published in peer-reviewed journals may diminish newsworthiness of scientific articles, but this issue has not been widely studied.Objective.—To analyze the impact on the news media, in terms of volume and prominence of coverage, of a scientific article published in peer-reviewed journals about issues with relevance to public health compared with the impact of preliminary release of information on the same issue.Design.—Analysis of press coverage of Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (mad cow disease) in the 7 newspapers with the widest circulation in Italy, between March 20, 1996, when the British secretary of state for health announced the identification of 10 cases of a new-variant CJD, described April 6, 1996, in The Lancet, and May 10, 1996. Related newspaper articles were identified by hand search.Main Outcome Measures.—Numbers of newspaper articles published before and after publication of the Lancet article.Results.—We collected 535 articles, of which 62 (11.6%) appeared on the front page. The number of articles published daily peaked on March 26 with 48 items and 1 article on the front page of all the newspapers. A total of 386 (72%) of the 535 articles and 56 (88.7%) of the 62 published on the front page were published in the first 2 weeks of the study period, before the Lancet publication.Conclusions.—Our analysis suggests that, in the case of issues of public health importance, when peer-reviewed research is published after a health risk is disclosed to the public, its impact in the media is small. Coordination between news release by public health authorities and publication by peer-reviewed journals may improve the quality of public information.JAMA. 1998;280:292-294
False-Positive Tests for Human Immunodeficiency Virus (HIV) in Patients with Cystic Fibrosis
Authors: Nicholas J. Dillman, Walter S. Ceglowski, Stanley B. Fiel
Journal: Annals of Internal Medicine (1989)

Letters and Corrections1 January 1989False-Positive Tests for Human Immunodeficiency Virus (HIV) in Patients with Cystic FibrosisNicholas J. Dillman, MD, Walter S. Ceglowski, PhD, Stanley B. Fiel, MDNicholas J. Dillman, MDSearch for more papers by this author, Walter S. Ceglowski, PhDSearch for more papers by this author, Stanley B. Fiel, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-110-1-94 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editor: The problem of false-positive enzyme immunoassay (EIA) tests for antibody to human immunodeficiency virus type 1 (HIV-1) is well documented (1-4). Particular groups of patients have been identified as having a greater incidence of false-positive assays. These groups include patients with systemic lupus erythematosus, rheumatoid arthritis, miscellaneous autoimmune diseases (1, 2), candidiasis, infectious mononucleosis (2), alcoholic hepatitis (1, 3), and hematologic malignancies (1, 2, 4).At our hospital, patients being considered for heart-lung transplants are routinely screened for antibody to HIV-1 by the EIA test. We report our observations concerning a group of patients with cystic fibrosis...References1. SteckelbergCockerille JF. Serologic testing for human immunodeficiency virus antibodies. Mayo Clin Proc. 1988;63:373-80. CrossrefMedlineGoogle Scholar2. . Human T-Lymphotropic Virus Type III. Abbott HTLV III EIA [Package insert]. 1987. Google Scholar3. MendenhallRoselleGrossmanRousterWeesnerDumaswala CGCSRU. False-positive tests for HTLV-III antibodies in alcoholic patients with hepatitis [Letter]. N Engl J Med. 1986; 314:921-2. CrossrefMedlineGoogle Scholar4. WeissGoedertSarngadharan SJM. Screening test for HTLV-III (AIDS agent) antibodies: specificity, sensitivity, and applications. JAMA. 1985;253:221-5. CrossrefMedlineGoogle Scholar5. Additional recommendations to reduce sexual and drug abuse-related transmission of human T-lymphotropic virus type III/lymphadenopathy associated virus. MMWR. 1986;35:152-5. MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: Nicholas J. Dillman, MD; Walter S. Ceglowski, PhD; Stanley B. Fiel, MDAffiliations: Temple University Hospital Philadelphia, PA 19140 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byCystic fibrosis 1 January 1989Volume 110, Issue 1Page: 94-94KeywordsCandidiasisCystic fibrosisEnzyme immunoassayHIVHIV-1Hematologic malignanciesInfectious diseasesInfectious hepatitisLupus erythematosusRheumatoid arthritis ePublished: 1 December 2008 Issue Published: 1 January 1989 PDF downloadLoading ...
Endocarditis Pathogen Promotes Vegetation Formation by Inducing Intravascular Neutrophil Extracellular Traps Through Activated Platelets
Authors: Chiau-Jing Jung, Chiou-Yueh Yeh, Ron-Bin Hsu, Chii-Ming Lee, Chia-Tung Shun, Jean-San Chia
Journal: Circulation (2014)

Background— Endocarditis-inducing streptococci form multilayered biofilms in complex with aggregated platelets on injured heart valves, but the host factors that interconnect and entrap these bacteria-platelet aggregates to promote vegetation formation were unclear. Methods and Results— In a Streptococcus mutans endocarditis rat model, we identified layers of neutrophil extracellular traps interconnecting and entrapping bacteria-platelet aggregates inside vegetation that could be reduced significantly in size along with diminished colonizing bacteria by prophylaxis with intravascular DNase I alone. The combination of activated platelets and specific immunoglobulin G–adsorbed bacteria are required to induce the formation of neutrophil extracellular traps through multiple activation pathways. Bacteria play key roles in coordinating the signaling through spleen tyrosine kinase, Src family kinases, phosphatidylinositol-3-kinase, and p38 mitogen-activated protein kinase pathways to upregulate the expression of P-selectin in platelets, while inducing reactive oxygen species–dependent citrullination in the arm of neutrophils. Neutrophil extracellular traps in turn serve as the scaffold to further enhance and entrap bacteria-platelet aggregate formation and expansion. Conclusions— Neutrophil extracellular traps promote and expand vegetation formation through enhancing and entrapping bacteria-platelet aggregates on the injured heart valves. (Circulation. 2015;131:571–581. DOI: 10.1161/CIRCULATIONAHA.114.011432.)
A SPECIFIC POISON IN THE LIVER EXTRACTS OF RABBITS INOCULATED WITH TYPHOID AND PRODIGIOSUS BACILLI INTRAVENOUSLY
Authors: Julia T. Parker
Journal: The Journal of Experimental Medicine (1918)

1. The livers of rabbits inoculated with cultures of Bacillus typhosus or Bacillus prodigiosus under certain conditions contain a toxic substance extractable with salt solution. When the toxic extracts are injected intravenously into normal rabbits the latter animals develop symptoms resembling those of anaphylactic shock and succumb. The lethal doses of the toxic extracts are far smaller than those of normal liver extract. 2. The livers of rabbits injected with typhoid antigen also yield a toxic extract. 3. Boiling as well as filtration through a Berkefeld filter only partially detoxicates the extract. 4. Tolerance to one to two lethal doses of the poisonous extracts can be induced by cautious immunization. 5. Rabbits actively immunized to Bacillus typhosus or Bacillus prodigiosus usually resist one lethal dose of the homologous liver poison; and animals tolerant to the typhoid liver poison resist one minimum lethal dose at least of Bacillus typhosus. 6. Typhoid immune serum is not detoxicating either in vivo or in vitro for the typhoid liver poison. 7. The liver poisons are specific, since rabbits actively immunized to either Bacillus typhosus or Bacillus prodigiosus withstand at least one minimum lethal dose of the homologous but not of the heterologous-liver poisons.
Epidemiologic determinants of skin photoaging: Baseline data of the SU.VI.MAX. cohort
Authors: J-M.Denis Malvy, Christiane Guinot, Paul Preziosi, Loc Vaillant, Michel Tenenhaus, Pilar Galan, Serge Hercberg, Erwin Tschachler
Journal: Journal of the American Academy of Dermatology (2000)