tbuckley/cabot-search huggingface dataset:
Abstract 4612: Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth.
Authors: Taro Hitosugi, Lu Zhou, Martha Arellano, Hanna Khoury, Titus Boggon, Sumin Kang, Chuan He, Jing Chen
Journal: Cancer Research (2013)

Abstract The current understanding of the Warburg effect consists of an increase in aerobic glycolysis in cancer cells. The connection between glycolysis and PPP/biosynthesis is based upon a model in which glycolytic intermediates can be diverted into PPP and biosynthesis pathways as precursors. However, it remains unclear how cancer cells coordinate glycolysis and biosynthesis to fulfill the request of rapidly growing tumors. We found that glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate (3-PG) and product 2-phosphoglycerate (2-PG). Our co-crystal structure based analysis revealed that 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP) as a competitive inhibitor, while 2-PG activates 3-phosphoglycerate dehydrogenase (PHGDH) to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth. These findings uncover that PGAM1 controls the intracellular 3-PG and 2-PG levels to serve as a novel link between glycolysis, biosynthesis, cancer cell proliferation and tumor development. Moreover, we screened and developed novel small molecule PGAM1 inhibitor (PGMI)-004A, which effectively inhibits PGAM1 enzyme activity, resulting in aberrant cancer cell metabolism with reduced glycolysis and PPP/anabolic biosynthesis, as well as attenuated cell proliferation in diverse human cancer cell lines, but not control normal human proliferating cells including human dermal fibroblasts and human foreskin fibroblasts. PGMI-004A treatment attenuates tumor growth in xenograft nude mice with minimal toxicity in vivo. Furthermore, PGMI-004A inhibits cell proliferation of primary leukemia cells from human AML, CML and B-ALL patients, but not control CD34+ cells isolated from bone marrow samples or mononucleocytes isolated from peripheral blood samples from healthy donors, suggesting minimal toxicity of PGMI-004A in human cells.These results together provide “proof of principle” for the development of PGAM1 inhibitors as anti-cancer agents. Citation Format: Taro Hitosugi, Lu Zhou, Martha Arellano, Hanna Khoury, Titus Boggon, Sumin Kang, Chuan He, Jing Chen. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4612. doi:10.1158/1538-7445.AM2013-4612
Hepatotoxicity of the Herbal Medicine Germander: Metabolic Activation of Its Furano Diterpenoids by Cytochrome P450 3A Depletes Cytoskeleton–Associated Protein Thiols and Forms Plasma Membrane Blebs in Rat Hepatocytes
Authors: M Lekehal, D Pessayre, J M Lereau, C Moulis, I Fourasté, D Fau
Journal: Hepatology (1996)

Several herbal remedies have produced hepatitis in humans. The medicinal plant, germander, was recalled after its use as an adjuvant to slimming diets resulted in an epidemic of hepatitis in France. We studied the hepatotoxicity of germander in isolated rat hepatocytes. A crude fraction containing the diverse furano diterpenoids of germander, or the purified main constituents of this fraction, teucrin A and teuchamaedryn A, were hepatotoxic (correction for hepatototoxic), but not fractions containing more polar or lipophilic constituents. [3H]Teucrin A covalently bound to hepatocyte proteins. The furano diterpenoid fraction decreased cell glutathione and cytoskeleton– associated protein thiols, and led to formation of plasma membrane blebs and cell demise. Pretreatment of male rats with troleandomycin, an inhibitor of cytochrome P450 3A (CYP3A), slowed the depletion of glutathione and decreased toxicity, whereas dexamethasone, an inducer of CYP3A, had opposite effects. Female rat hepatocytes, which poorly express CYP3A, exhibited little toxicity, unless the animals were treated with dexamethasone. Feeding male rats with a sulfur amino acid– deficient diet decreased cell glutathione and enhanced toxicity, whereas supplementation of the standard diet with cystine had opposite effects. We conclude that the furano diterpenoids of germander are activated by CYP3A into electrophilic metabolites that deplete glutathione and cytoskeleton–associated protein thiols and form plasma membrane blebs. We suggest that studies in isolated hepatocytes be included in the preclinical assessment of herbal remedies.
Government to press trusts to meet screening targets for chlamydia
Authors: Caroline White
Journal: BMJ (2008)

The Department of Health is to increase pressure on trusts that are not on course to meet the target of screening 15% of 15-24 year olds for chlamydia by the end of March this year.

Figures released by the Health Protection Agency last November showed that the best performing strategic health authority had only managed 2.5% by September 2007 ( BMJ 2007;335:1010; doi: 10.1136/bmj.39398.715324.DB).

The latest figures, which are due to be released next week, are expected to show an improvement, but not sufficient to allay concerns about the target being …
Inhibition of Hepatic Binding of Thyroxine by Cholecystographic Agents
Authors: James V. Felicetta, William L. Green, Wil B. Nelp
Journal: Journal of Clinical Investigation (1980)

Subsequent to studies indicating that cholecystographic agents and sulfobromophthalein (BSP) inhibit uptake of thyroxine (T4) by rat liver slices, the effect of such compounds on hepatic storage of T4 in man has been examined. After intravenous administration of [125I]T4 to five normal subjects, hepatic radioactivity, estimated by external gamma counting, rose to a peak in ∼4 h and then declined in parallel with serum radioactivity. When a 6-g dose of the cholecystographic agent, tyropanoate (Bilopaque), was administered orally 3 d later, estimated hepatic extravascular radioactivity fell 50-60% within 4 h and then rose toward the pretyropanoate value. Concomitant with the fall in hepatic radioactivity, serum radioactivity rose 57-70%, as did stable T4 levels in serum, suggesting that hormone discharged from the liver entered the serum. Both uptake of T4 and discharge by tyropanoate were much less in two patients with liver disease.
Book Review Sun-Damaged Skin By Ronald Marks. 72 pp., illustrated. London, Martin Dunitz, 1992. £14.95. 1-85317-077-1 The Environmental Threat to the Skin Edited by Ronald Marks and Gerd Plewig. 414 pp., illustrated. London, Martin Dunitz, 1992. £65. 1-85317-057-7
Authors: Lynn A. Drake
Journal: New England Journal of Medicine (1993)
The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region
Authors: K A van Schie, M H Hart, E R de Groot, S Kruithof, L A Aarden, G J Wolbink, T Rispens
Journal: Annals of the Rheumatic Diseases (2014)

Background In a subset of patients, anti tumour necrosis factor (TNF) therapeutic antibodies are immunogenic, resulting in the formation of antidrug antibodies (ADAs). Neutralising ADAs compete with TNF for its binding site and reduces the effective serum concentration, causing clinical non-response. It is however unknown to which extent ADAs are neutralising. Objectives To study which proportion of antibodies to human(ised) anti-TNF (adalimumab, golimumab, certolizumab) as well as chimeric anti-TNF (infliximab) is neutralising. Methods Neutralising capacity of ADAs was assessed using a TNF competition assay in ADA-positive sera of patients treated with adalimumab (n=21), golimumab (n=4), certolizumab (n=9) or infliximab (n=34) sent in to our diagnostic department. Results In 34 sera with ADAs to adalimumab, golimumab or certolizumab, &gt;97% of the antibodies were neutralising. In 34 sera with ADAs to infliximab &gt;90% of the antibodies were neutralising. Further characterisation of the broader antibody response to infliximab revealed that non-neutralising antibodies to infliximab do not target murine domains, but may bind infliximab-unique domains not involved in TNF binding (located outside the paratope). Conclusions Our study shows that ADAs to human(ised) as well as chimeric anti-TNF therapeutic antibodies are largely neutralising. This highly restricted ADA response suggests an immunodominant role for the paratope of anti-TNF therapeutics.
Identification of Major Prognostic Subgroups of Patients with Large-Cell Lymphoma Treated with m-BACOD or M-BACOD
Authors: MARGARET A. SHIPP
Journal: Annals of Internal Medicine (1986)

One hundred twenty-one patients with diffuse large-cell lymphoma treated with m- or M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) were evaluated for pretreatment characteristics predictive for response and survival. Two characteristics, poor performance status and massive bulky disease, were negatively associated with response rate in a multivariate analysis. These two characteristics were also negatively associated with survival in multivariate analysis, as was another factor, an increased number of extranodal sites of disease. These three pretreatment characteristics were used to construct a model containing 12 categories of patients at increasing risk for relapse and shortened survival. These categories divided naturally into three broad groups of patients with respective 5-year survival rates of 68%, 55%, and 24%.
831 OUTCOME PREDICTION MODELS TO DETERMINE THE INDICATIONS OF LIVER TRANSPLANTATION IN PATIENTS WITH ACUTE LIVER FAILURE: DATA MINING USING DECISION TREE LEARNING AND RBF NETWORK
Authors: N. Nakayama, S. Nagoshi, K. Fujiwara, M. Oketani, H. Tsubouchi, Y. Kawamura, S. Mochida
Journal: Journal of Hepatology (2010)
Radiopaque fluorescence-transparent TaO decorated upconversion nanophosphors for in vivo CT/MR/UCL trimodal imaging
Authors: Qingfeng Xiao, Wenbo Bu, Qingguo Ren, Shengjian Zhang, Huaiyong Xing, Feng Chen, Ming Li, Xiangpeng Zheng, Yanqing Hua, Liangping Zhou, Weijun Peng, Haiyun Qu, Zheng Wang, Kuaile Zhao, Jianlin Shi
Journal: Biomaterials (2012)
THE RENAL HUMORAL PRESSOR MECHANISM IN MAN. I. PREPARATION AND ASSAY OF HUMAN RENIN, HUMAN HYPERTENSINOGEN, AND HYPERTENSIN 12
Authors: Lewis Dexter, Florence W. Haynes, William C. Bridges
Journal: Journal of Clinical Investigation (1945)

Human renin and hypertensinogen differ from those of animal origin in certain properties which make their preparation and assay by current technics unsatisfactory, principally due to the presence of hypertensinase.Their method of preparation, in a form free from hypertensinase but not chemically pure, and their assay are the subjects of this communication.
The Making of a Social Disease: Tuberculosis in Nineteenth-Century France
Authors: Ruben D. Rumbaut
Journal: JAMA (1996)

<i>The Making of a Social Disease</i>is not written by a physician but by an assistant professor of liberal arts. It is not a clinical text, but a historical one; not about America, but France; not about our times, but the years from 1819 to 1919; and not about infectious diseases in general, but just tuberculosis (TB). And yet, it is an absorbing, well-written, superbly researched, thought-provoking, useful, and magisterial book. Because its subject is intemporal and universal, we all can learn from it. There seems to be something ancestral, almost archetypal, in the reactions of individuals and societies to the presence of any serious disease. Why me? Are the gods or the demons angry? Have we broken any taboo, code, law? Is this punishment deserved? Who is to blame? How did we get it? Will the suffering be intense or long or end in death? What is the meaning
Penile injuries from vacuum cleaners.
Authors: N D Citron, P J Wade
Journal: BMJ (1980)

Salmonella hadar peritonitisIn September 1979 an outbreak of food poisoning at a Norfolk holiday camp was caused by Salmonella hadar.Most of the 500 patients had mild diarrhoea and vomiting and were treated at the camp.Nevertheless, 30 became severely dehydrated and were admitted to hospital.Two of these patients subsequently developed S hadar peritonitis, a condition that has not been described. Case reportsCase 1-A 78-year-old woman was admitted after two days' profuse diarrhoea.She had a history of congestive cardiac failure and rheumatic mitral stenosis, and was clinically dehydrated and feverish (386°C) with controlled atrial fibrillation.Haemoglobin 10-7 g/dl, white cell count 7-9 x 109/1, blood urea concentration 7-8 mmol/l (47 mg/100 ml).S hadar was cultured from faeces.The patient was treated intravenously with fluids and antidiarrhoeal agents but on day 6 developed abdominal tenderness and distension.Her general condition deteriorated and x-ray examination showed free intraperitoneal gas.At laparotomy there was diffuse peritonitis and the ascending colon was particularly friable with multiple tiny perforations exuding fluid faeces.A right hemicolectomy was performed, the divided ends were ulcerated, oedematous, and friable, and unsuitable for primary anastomosis.The terminal ileum and proximal end of the transverse colon were brought out through the abdominal wall.Despite ventilation and intensive care she died 18 hours later.Case 2-An 81-year-old woman-was admitted after four days' diarrhoea.She had had a myocardial infarction and congestive cardiac failure and was clinically dehydrated and in atrial fibrillation.Haemoglobin was 14-4 g/dl, white cell count 68 x 109/1, and blood urea concentration 26-2 mmol/l (157 mg/100 ml).S hadar was isolated from faeces.The patient responded well to rehydration and antidiarrhoeal agents.On day 7 her abdomen became tender and distended with no bowel sounds.Abdominal x-ray examination showed dilated loops of bowel with fluid levels.Her condition deterior- ated and at laparotomy 48 hours later she had gross peritonitis with acute inflammation of the jejunum, ileum, and appendix with multiple small perforations.Two separate segments of ileum were resected and-appendicectomy performed.The cut ends were friable and oedematous; neverthe- less, one end-to-end anastomosis was performed and two ends were brought out as separate ileostomies.She was ventilated and intravenously fed, but died of acute on chronic renal failure four weeks later.Histology of the resected bowel showed focal and confluent areas of mucosal necrosis not associated with Peyer's patches.There was extensive infiltration with histiocytes and polymorphs.The sites of perforation could not be demon- strated microscopically.The patient had salmonella endocarditis of the mitral valve.
Abstract 2371: Heterogeneity of resistance mechanisms in lung adenocarcinoma patients with acquired resistance to EGFR inhibitors
Authors: Xinmeng Jasmine Mu, Eli Van Allen, Nikhil Wagle, Curtis Chong, Mohit Butaney, Deborah Farlow, Gad Getz, Pasi A. Jänne, Levi A. Garraway
Journal: Cancer Research (2014)

Abstract Drug resistance is a major obstacle in overcoming cancer. Understanding the origin, extent and heterogeneity of resistance mechanisms within a patient is crucial to guide treatment and developing drugs/combinations to circumvent resistance. To this end, we studied autopsy samples collected from four EGFR-mutant lung adenocarcinoma patients who developed resistance to EGFR inhibitors. We used whole-exome sequencing to characterize genomic profiles of multiple metastasis tumors within each patient. To address the challenge of non-uniform variant detection power at sequenced genetic loci across multiple samples, we developed a computational framework that tackles variant detection from pooled tumor followed by a genotyping module. After the identification of somatic alterations, we determined the extent of heterogeneity of resistance mechanisms between multiple tumor samples. Our results revealed that multiple metastasis samples in a single patient can potentially use one common resistance mechanism. For example, one patient harbored a resistant EGFR T790M mutation in all 11 metastasis samples with a correlated allele frequency to the original L858R mutation. However, in some other cases, we found heterogeneous resistance mechanisms coexisting in multiple metastasis samples with various allele frequencies. For instance, one patient harbored both the resistance EGFR T790M mutation and an activating PIK3CA E542K mutation that appear with a range of allelic frequencies in multiple metastatic samples. Furthermore, branched evolutionary patterns of tumors were constructed using a phylogenetic approach, which inform resistance in the context of tumor evolution. Our findings are consistent with the model that cells harboring a variety of resistance mechanisms coexist in each metastasis tumor, and those subclones with higher selective advantage outgrow the others. Citation Format: Xinmeng Jasmine Mu, Eli Van Allen, Nikhil Wagle, Curtis Chong, Mohit Butaney, Deborah Farlow, Gad Getz, Pasi A. Jänne, Levi A. Garraway. Heterogeneity of resistance mechanisms in lung adenocarcinoma patients with acquired resistance to EGFR inhibitors. [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 2371. doi:10.1158/1538-7445.AM2014-2371
Skin rashes and stomatitis due to parenteral treatment of rheumatoid arthritis with sodium aurothiomalate.
Authors: A Svensson, J Theander
Journal: Annals of the Rheumatic Diseases (1992)

In a prospective study of 45 patients with rheumatoid arthritis mucocutaneous symptoms and signs were evaluated before and during treatment with intramuscular sodium aurothiomalate (Myocrisin). The work, performed in close collaboration between dermatology and rheumatology departments, showed that there was no significant increase in mucocutaneous side effects in patients with pre-existing mucocutaneous disease. It is concluded that pre-existing dermatitis is not a contraindication for treatment with gold salts and that a previous mucocutaneous reaction to gold salts is not an absolute contraindication for a new trial of chrysotherapy.
In-Flight Pilot Incapacitation
Authors: John P. McCann, Victor E. Schulze
Journal: JAMA (1963)

DURING THE YEARS 1959, 1960, and 1961, the Air Training Command of the US Air Force flew a total of 3,606,787 hr, two thirds of which were in jet-type aircraft.<sup>1</sup>In these 3 yr, there were 53 fatal accidents, of which 51 were in jet aircraft. In 18 of the fatal accidents, some sort of physical incapacitation of the pilot was suggested, and in 5 of these cases, physical incapacitation was the probable cause of the accident.<sup>2</sup>Fifty-three fatal accidents appears to be a large figure; when considered in light of total hours flown, however, it compares well with the current fatality rate per 100,000 flying hours, which is now at a low of 1.4. This figure reflects a continuing improvement, with recorded rates of 8 in 1947 and 55 in 1921.<sup>3</sup>This safety record is even more striking when one realizes that most of the
Factors determining spontaneous histamine release from human basophils purified with Percoll gradients and Dynabeads
Authors: H. V. Nielsen, P. M. Shah, P. O. Schietz
Journal: Allergy (1998)

Identification of factors influencing histamine release from purified and cultured basophil leukocytes is important for proper interpretation of results obtained on histamine release. This paper describes factors that influence spontaneous histamine secretion from human basophil leukocytes purified on Percoll gradients, followed by negative selection with Dynabeads. Anti-IgE and recombinant human interleukin-3 were used as model stimulants, and the purified basophil leukocytes were stimulated for 10 min and 6 h. The effect of the following conditions was examined: Percoll temperature, cell-suspension density, and serum in the media. The results showed that low Percoll temperature, high cell-suspension density, and the presence of serum in the media decreased spontaneous histamine release and increased maximal net histamine release upon stimulation.
Dyspepsia: incidence of a non-ulcer disease in a controlled trial of ranitidine in general practice.
Authors: J H Saunders, R J Oliver, D L Higson
Journal: BMJ (1986)

Patients who presented to their family doctors with previously uninvestigated dyspepsia of at least two weeks9 duration were recruited into a placebo controlled trial of treatment with ranitidine (150 mg twice daily) for six weeks. All patients were examined by endoscopy before treatment, and for those with macroscopical abnormalities the examination was repeated after treatment. Of the 604 patients recruited, 559 had endoscopy, of whom 171 (30%) had no apparent abnormality. Of the 388 patients remaining, one third had two or more lesions. The high incidence of underlying disease was coupled with low accuracy in unaided clinical diagnosis. After endoscopy 496 patients with persistent symptoms (median duration six to eight weeks) were randomly allocated to treatment and then reviewed every two weeks. Complete remission of symptoms occurred in 76% of patients who were taking ranitidine and in 55% who were taking placebo (p less than 0.000004). Of those with non-ulcer dyspepsia, significantly more became symptom free taking ranitidine compared with placebo (p less than 0.002). Ranitidine healed most duodenal ulcers (80%) and gastric ulcers (90%) within four weeks. Tolerance to ranitidine was good, and the incidence of complaints was similar on placebo.
Contact Wounds: A War Surgeon's Education
Authors: Richard Villar
Journal: BMJ (2006)

W ork in any conflict zone and you will run into a diversity of interesting characters. By no standards can medicine in such an environment be regarded as normal. It is uncomfortable, dangerous, unpredictable, and frequently lonely. It is invariably low paid. There is also an almost unwritten rule that no one asks a colleague why he or she has ended up working in such a situation. So often there has been some drama at home—divorce, bereavement, or repossession, scenarios that we all wish to avoid.

I remember an SAS officer once telling me that the SAS was a “bunch of misfits who happened to fit together.” What an apt description that was. Conflict zones seem a perfect escape for such people. So, as I opened the …
TCT-97 Long term follow up of 134 patients with non valvular atrial fibrillation and contraindications to oral anticoagulation therapy, treated with the Ampatzer Cardiac Plug Device for left atrial appendage occlusion
Authors: Miroslava Stolcova, Marco Rezzaghi, Francesco Meucci, Cataldo Palmieri, Umberto Paradossi, Luigi E. Pastormerlo, Gabriele Rosso, Sergio Berti, Gennaro Santoro
Journal: Journal of the American College of Cardiology (2013)