tbuckley/cabot-search huggingface dataset:
Abstract 3420: TERT promoter mutations are rare in uveal melanoma
Authors: Adriana Agnese AMARO, Marina Gualco, Maria Dono, Ulrich Pfeffer, Irena Maric, Carlo Mosci
Journal: Cancer Research (2014)

Abstract Uveal melanoma is the most frequent primary tumor of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight UV-exposure on the etiology of uveal melanoma is matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma. We also analyzed the frequency of other recently discovered uveal melanoma specific mutations in the genes GNAQ, GNA11, BAP1, SF3B1, and EIFAX1, and we analyzed the association of these mutation with histopathological and clinical features including progression free survival. Finally, we analyzed TERT expression in these tumors. The mutation frequencies observed confirmed the prevalence of GNAQ mutations in cases with disomy of chromosome 3 that have a better prognosis whereas GNA11 was more frequent in monosomic cases. Together these two mutations account for more than 85% of the cases. BAP1 mutations are associated with chromosome 3 monosomy but not with progression free survival. SF3B1 and EIF1AX mutations occur in 10.3 and 22.5% of uveal melanomas, in disomic cases only. We detected a TERT mutation in only one case of a 57-year old white male with clinical and histo-pathological features typical for uveal melanoma. The tumor showed mutations in GNA11 and EIF1AX. No mutations were detected in GNAQ, BAP1, and SF3B1. Both copies of chromosome 3 were retained. Several tumors among which the one carrying the TERT promoter mutation showed elevated TERT expression. These data indicate that TERT mutations are rare in uveal melanoma, consistent with a reduced etiological influence of sunlight. No conclusion can be drawn on the potential influence of TERT mutations on tumor progression. Citation Format: Adriana Agnese AMARO, Marina Gualco, Maria Dono, Ulrich Pfeffer, Irena Maric, Carlo Mosci. TERT promoter mutations are rare in uveal melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3420. doi:10.1158/1538-7445.AM2014-3420
Gram-Negative-Rod Bacteremia
Authors: Sheldon M. Wolff, John V. Bennett
Journal: New England Journal of Medicine (1974)

The incidence of gram-negative-rod bacteremia has increased during the past two decades.1 A recent paper estimated that there may be as many as 300,000 cases per year in the United States, with approximately 100,000 deaths resulting from this disease.2 Furthermore, the increasing use of antimicrobial agents has been implicated as a major contributory factor in the development of gram-negative-rod bacteremia. In a paper earlier this year,3 the possible relation of antibiotic overuse and misuse to the development of such infections was emphasized. As a result of these concerns, the Subcommittee on Health of the Committee on Labor and Public Welfare . . .
Studies in the Epidemiology of Tinea Pedis: IV. Seed and Soil
Authors: M. P. English, M. D. Gibson, E. H. L. Duncan
Journal: BMJ (1960)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Studies in the Epidemiology of Tinea Pedis Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
343. Repair of Thalassemic β-Globin pre-mRNA by Antisense AAV and Lentiviral Vectors in Cell Culture
Authors: Thipparat Suwanmanee, Vivian W. Choi, Richard J. Samulski, Tal Kafri, Ryszard Kole
Journal: Molecular Therapy (2005)

b-Thalassemia is a worldwide genetic blood disorder characterized by a deficiency or lack of the b-globin chain production. More than 200 mutations in the b-globin gene are responsible for this disease. Several common mutations create aberrant splice sites in the b-globin pre-mRNA, leading to an incorrectly spliced b-globin mRNA. Previous study in this lab showed that a modified U7.623 snRNA, which carries a specific sequence antisense to the splicing enhancer sequence of the three b-thalassemic mutants (IVS2-654, -705, and -745), could modify the splicing pathway and restore correctly spliced b-globin mRNA and protein in cell culture. In this study we incorporated the U7.623 antisense snRNA into lentiviral- and AAV-vectors. Transient transfection of HeLa cell lines expressing IVS2-654, and-705, with an AAV-U7 antisense snRNA plasmid, resulted in a restoration of both correctly spliced b-globin mRNA and full-length b-globin polypeptide. The results show that antisense snRNAs shifted the splicing pathway from aberrant to correct and restored the correct mRNAs in a sequence specific and dose-dependent manner. This was accomplished in model cell lines, in which the thalassemic b-globin intron was incorporated into the enhanced green fluorescence protein (EGFP) coding sequence and in HeLa cells that express thalassemic human b-globin genes. Transfection of EGFP-HeLa cell lines with IVS2-654, and -705U introns with AAV-U7.623 resulted in upregulation and expression of EGFP protein concomitant with expression of the of red fluorescence protein (RFP), an AAV viral reporter gene. Similar results, although less pronounced, were obtained in cells transiently transfected with lentiviral-U7.623 antisense snRNA construct. Interestingly, the restoration of correctly spliced mRNAs was faster in AAV than lentiviral vector treated cells. Based on this encouraging result, the AAV- and lentiviral-U7 antisense snRNA constructs will be evaluated in animal models for thalassemia. The snRNA antisense-based gene therapy may offer an attractive approach to cure thalassemia.
Impact of the Underlying Mutation and the Route of Vector Administration on Immune Responses to Factor IX in Gene Therapy for Hemophilia B
Authors: Ou Cao, Brad E Hoffman, Babak Moghimi, Sushrusha Nayak, Mario Cooper, Shangzhen Zhou, Hildegund CJ Ertl, Katherine A High, Roland W Herzog
Journal: Molecular Therapy (2009)

Immune responses to factor IX (F.IX), a major concern in gene therapy for hemophilia, were analyzed for adeno-associated viral (AAV-2) gene transfer to skeletal muscle and liver as a function of the F9 underlying mutation. Vectors identical to those recently used in clinical trials were administered to four lines of hemophilia B mice on a defined genetic background [C3H/HeJ with deletion of endogenous F9 and transgenic for a range of nonfunctional human F.IX (hF.IX) variants]. The strength of the immune response to AAV-encoded F.IX inversely correlated with the degree of conservation of endogenous coding information and levels of endogenous antigen. Null mutation animals developed T- and B-cell responses in both protocols. However, inhibitor titers were considerably higher upon muscle gene transfer (or protein therapy). Transduced muscles of Null mice had strong infiltrates with CD8+ cells, which were much more limited in the liver and not seen for the other mutations. Sustained expression was achieved with liver transduction in mice with crm(-) nonsense and missense mutations, although they still formed antibodies upon muscle gene transfer. Therefore, endogenous expression prevented T-cell responses more effectively than antibody formation, and immune responses varied substantially depending on the protocol and the underlying mutation.
Genetic analysis of autoimmune gld mice. I. Identification of a restriction fragment length polymorphism closely linked to the gld mutation within a conserved linkage group.
Authors: M F Seldin, H C Morse, J P Reeves, C L Scribner, R C LeBoeuf, A D Steinberg
Journal: The Journal of Experimental Medicine (1988)

A linkage map of distal mouse chromosome 1 was generated using restriction fragment length polymorphism (RFLP) analysis of DNA prepared from 95 [C3H-gld/gld X Mus spretus)F1 X C3H-gld/gld] backcross mice. The gene order was: (centromere) C4bp, Ren-1,2, Ly-5, [At-3/gld], Apoa-2/Ly-17, Spna-1 (telomere). All mice expressing the phenotype of gld homozygotes were homozygous for the At-3 RFLP characteristic of C3H mice and none of the mice heterozygous for At-3 RFLPs had characteristics of gld homozygotes, demonstrating close linkage between these genes. The identification of an RFLP closely linked to the gld gene provides a starting point for the identification of a genetic defect that results in abnormal T cells and autoimmune disease.
Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections
Authors: V Baeyens, V Kaltsatos, B Boisramé, E Varesio, J.-L Veuthey, M Fathi, L.P Balant, M Gex-Fabry, R Gurny
Journal: Journal of Controlled Release (1998)
Does Simple Mastectomy Followed by Irradiation Offer Survival Comparable to Radical Procedures?
Authors: Sigvard Kaae
Journal: JAMA (1967)

During the past two decades many hospitals have been increasing the use of radiotherapy in breast cancer in operable stages. The most widespread method is simple mastectomy followed by irradiation. This method has been systematized mainly by McWhirter,<sup>16</sup>who uses it in all cases of operable breast cancer and in a number of inoperable cases, too. His therapeutic results are good, but a reliable comparison of his own results with those of radical mastectomy has not been possible. McWhirter states that the therapeutic results of radical mastectomy are excellent when the axillary nodes are not involved, but if there are no malignant cells in the axilla it would appear unnecessary to dissect it. On the other hand, when the axilla is secondarily involved, there is universal agreement that radical mastectomy often fails to save the patient's life. It is generally agreed that the prognosis following radical mastectomy in cases
Physicians as Leaders in the Improvement of Health Care Systems
Authors: James L. Reinertsen
Journal: Annals of Internal Medicine (1998)

Physicians are often asked to assume leadership roles in their practices, hospitals, and academic departments.These positions can be excellent leverage points for improvement of health care quality. To make optimal use of these opportunities, physicians must learn how to lead. This paper is intended to be a primer for physicians who are asked to lead and want to learn how to lead well. A body of knowledge that physician-leaders should acquire is described, and case examples are used to address such topics as the nature of leadership, the relation between leadership and management, and ways in which physicians might approach a new leadership assignment. Guidelines for physicians who must play the role of followers are offered, and challenges that physicians who lead other physicians may face are described.
A PLAN TO MODIFY THE JAPANESE JINRIKISHA INTO A WHEELED LITTER FOR REMOVING THE WOUNDED IN BATTLE.
Authors: EDMUND ANDREWS
Journal: JAMA (1898)

Twenty-eight years ago a great industrial revolution occurred in Japan. It was nothing less than a total change in the ancient vehicles employed in the transportation of passengers. Wheeled carriages had seldom or never been used before this. A few officials rode on horseback. The usual plan was for the poor to go on foot and the rich to hire coolies who carried them litter-fashion in sedan chairs and cagos. The cago was a kind of litter suspended to a pole and carried on the shoulders of two coolies. As this is very exhausting labor each coolie carried also a stick as long as from his shoulder to the ground. When they found it necessary to rest they set these sticks upright under the ends of the pole, thus relieving them from the weight. Men of means traveling to a distant destination hired four or six coolies, who relieved each
Pulmonary Immunity to <i>Listeria</i> Is Enhanced by Elimination of Alveolar Macrophages
Authors: RICHARD L. KRADIN, HONG-WEN LIU, NICO van ROOIJEN, KIM SPRINGER, LONG-HAI ZHAO, CAROL P. LEARY
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

To determine how resident alveolar macrophages (AM) regulate the antigen-presenting–cell (APC) activities of pulmonary dendritic cells (DC) in the response to particulate antigen, we pretreated Lewis rats intratracheally with liposomes containing clodronate (LIP-CLOD), which eliminated AM in vivo. Controls received saline encapsulated in liposomes (LIP-SAL) or saline alone intratracheally. At Day 3, rats were injected intratracheally with 1 × 107 heat-killed Listeria (HKL) and DC purified from lung were examined for their ability to stimulate HKL-immune T cells without added HKL. Only DC from LIP-CLOD–treated rats displayed enhanced APC activities for HKL. A second intratracheal HKL challenge at Day 14 yielded lymphocytic cuffing of the microvasculature in LIP-CLOD–treated lungs only. Intratracheal adoptive transfer of normal syngeneic AM into LIP–CLOD–treated rats suppressed APC activities of DC in vitro and the lymphocytic response in vivo. Bronchoalveolar macrophages from rats treated with LIP-CLOD and HKL showed decreased production of nitric oxide (NO), a potent suppressor of DC and T-helper 1 lymphocyte activities as compared with those of controls. We conclude that eliminating AM in vivo reduces local production of NO and promotes pulmonary cell-mediated immunity to HKL.
A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis
Authors: Emmanuel Somm, Nicolas Bonnet, Alberto Martinez, Philip M.H. Marks, Verity A. Cadd, Mark Elliott, Audrey Toulotte, Serge L. Ferrari, René Rizzoli, Petra S. Hüppi, Elaine Harper, Shlomo Melmed, Richard Jones, Michel L. Aubert
Journal: Journal of Clinical Investigation (2012)

Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2–amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.
Amphotericin B
Authors: Gerald Medoff
Journal: JAMA (1975)

RECENT animal experiments<sup>1-4</sup>support our earlier in vitro work on the synergistic action of amphotericin B and second agents against a variety of fungi.<sup>5-9</sup>Before these results lead to the indiscriminate use of amphotericin B and flucytosine for the treatment of all fungal infections in human beings, we would like to review some old and recent information, which might encourage some circumspection in the use of combination therapy. Amphotericin B is a polyene macrolide that binds to sterols in eukaryotic cell membranes.<sup>10</sup>It is the only polyene antibiotic that is sufficiently nontoxic to be useful itself in the treatment of systemic fungal infections. The relative specificity of amphotericin B for fungi is likely due to its greater avidity for ergosterol, the principal sterol in fungal cell membranes, than cholesterol, the principal sterol in animal cell membranes.<sup>11</sup>Unfortunately, the specificity of amphotericin B for fungi compared to animal
Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes
Authors: Peter A. Gottlieb, Scott Quinlan, Heidi Krause-Steinrauf, Carla J. Greenbaum, Darrell M. Wilson, Henry Rodriguez, Desmond A. Schatz, Antoinette M. Moran, John M. Lachin, Jay S. Skyler
Journal: Diabetes Care (2010)

OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.
Amyotrophy and Herpes Zoster
Authors: Gerald W. Parker
Journal: JAMA (1962)

To the Editor:—  Motor manifestations do occur in zoster; the histopathologic findings support the concept that they should occur, and that they are probably more common than realized. Awareness on the part of the physician is only necessary in order to detect the motor phenomena.  As a point of interest, let me tell you about a few incidents which have been brought to light at this medical center. Capt. Roger C. Duvoisin, Chief of Neurology, related a case to me of a middle-aged father who complained of a left foot drop. He had neuritic pain in the buttock, one small vesicle on the left buttock, and had been exposed to varicella (his children) a week or so before the onset of his foot drop. Dr. Duvoisin felt sure that the problem was one of zoster. Capt. Frank Lecocq, Chief of Metabolic Service, recently saw a young lady who complained of
US scientists discuss early detection and treatment of Alzheimer's disease
Authors: J. H. Tanne
Journal: BMJ (2012)

The US president, Barack Obama, has announced an increase in funding for Alzheimer’s disease next year of $106m (£67m; €80m), a 24% rise over the current $450m a year.

The announcement came shortly after scientists gathered at a meeting of the New York Academy of Sciences in New York to try to determine how best to spot Alzheimer’s disease in the “silent years” before the disease is apparent.

Reisa Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, Boston, said, “The pathophysiology begins more than a decade before dementia . . . We are trying to define the earliest markers for the ‘iceberg’ silent years when preclinical changes are …
<i>g</i> and Darwinian algorithms
Authors: Kevin MacDonald, David Geary
Journal: Behavioral and Brain Sciences (2000)

Stanovich &amp; West's assumption of discrete System 1 and System 2 mechanisms is questionable. System 2 can be understood as emerging from individuals who score high on several normally distributed cognitive mechanisms supporting System 1. Cognitions ascribed to System 1 and System 2 appear to be directed toward the same evolutionary significant goals, and thus are likely to have emerged from the same selection pressures.
A CASE OF IMPERFORATE RECTUM WITH ABSENCE OF THE ANUS.
Authors: EDWARD H. SMALL
Journal: JAMA (1905)

Oct. 25, 1903, R. K., male, was born under my care. His mother had already given birth to four other children, all perfectly formed. He was born at full term, head presentation, R. O. A. No anus at all was to be seen. The raphe ran from the base of the scrotum to the tip of the coccyx. There was phimosis and the second and third toes of both feet were webbed. There was a slight dimple in the medium line of the back over the center of the sacrum. The base of the penis was drawn toward the scrotum, making it much longer anteriorly than posteriorly. The mother is disposed to attribute these malformations to a rather severe felon she had seven months before the child's birth. When the boy was 30 hours old he was held in the exaggerated lithotomy position, and, without the use of anesthesia, a
UK survey finds variation in oestrogen receptor testing
Authors: Susan Mayor
Journal: BMJ (2001)

Differences in the methods used for oestrogen receptor testing in women with breast cancer may mean that some miss out on optimal treatment, a survey of breast cancer units in the United Kingdom reported last week.

The postal survey of 229 breast cancer units throughout Britain showed that only a third of centres were testing oestrogen receptor status by what breast cancer specialists consider to be the most accurate method.

Reporting the findings, Mr Gordon Wishart, consultant breast surgeon at the breast unit of Addenbrooke's Hospital, Cambridge, said: “Accurate knowledge of oestrogen receptor status is …
CAFFEIN INTRAVENOUSLY—THE BEST OF STIMULANTS
Authors: W. W. DUKE
Journal: JAMA (1923)

In discussing the use of caffein as a stimulant, I wish to discuss it as a stimulant only, not as a permanent remedy. As a temporary stimulant, it is the one and only drug which in my experience never completely fails. Stimulants such as strychnin, atropin, strophanthin, digitalis intravenously, and the weak member camphorated oil have the unhappy faculty of usually failing when they are most needed—that is, in desperately ill patients. This we should expect. The poisons elaborated in many diseases are so much more potent than drugs that, in the majority of such cases, stimulating drugs seem to amount to little more than the water in which they are dissolved. Caffein does not come in this class, however, if given intravenously. If given subcutaneously, it fails as other stimulants do. My attention was first drawn to its usefulness by a case observed when I was a house officer