tbuckley/cabot-search huggingface dataset:
Abstract 2800: Dual PI3K/mTOR inhibitor NVP BEZ-235 suppresses translation of hypoxia-inducible factor (HIF)-1α and increases cell death under hypoxia
Authors: Jayashree Karar, George J. Cerniglia, Constantinos Koumenis, Amit Maity
Journal: Cancer Research (2012)

Abstract Our goal was to investigate the effects of the Novartis compound NVP-BEZ235, a dual PI3K/mTOR inhibitor, on hypoxia-inducible factor-1 alpha (HIF-1α) expression. NVP-BEZ235 was much more potent than either the mTOR inhibitor rapamycin or the PI3K inhibitor LY294002 in blocking the hypoxic induction of HIF-1α in vitro, due to decreased protein translation. 7-methyl GTP chromatography showed that NVP-BEZ235 led to a robust recruitment of 4E-BP1 to eIF4E and a near absence of binding of eIF4G, consistent with inhibition of protein translation. NVP-BEZ235 also decreased expression of several proteins regulated by eIF4E including cyclin B1 and D1, survivin, and vascular endothelial growth factor. NVP-BEZ235 specifically decreased eIF4G but not eIF4E expression. As HIF-1α has been associated with adaptation under hypoxia, we examined the effect of NVP-BEZ235 on cell survival in low pO2 conditions. The drug increased killing of cells under hypoxia as measured by both short-term (MTT) and long-term (clonogenic) assays. To understand the mechanism behind this observation, we performed immunoblotting for factors associated with cell survival. In normoxia, Akt S473 phosphorylation decreased within an hour of NVP-BEZ235 treatment, but then increased by 24 hours. In contrast, under hypoxia, NVP-BEZ235 caused a prolonged suppression of Akt phosphorylation. Furthermore, we found a greater increase in PARP cleavage in hypoxic cells treated 1-16 hours after drug treatment than in normoxic cells, consistent with increased apoptosis. This was confirmed using an ELISA assay that measures cytoplasmic oligonucleosomes. We also found that NVP-BEZ235 increases autophagy as measured by (i) LC3-I to LC3-II conversion on immunoblotting, (ii) degradation of p62 and (iii) GFP-LC3 subcellular localization detected by immunofluorescence. Treatment of cells with the drug under hypoxia further increased autophagy, although it is unclear at this point whether this actually contributes to cell death or is a pro-survival mechanism. In conclusion, we have found that NVP-BEZ235 blocks HIF-1α induction and increases cell killing under hypoxia, which may have important implications for the use of this drug in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2800. doi:1538-7445.AM2012-2800
Radiation Therapy and Adjuvant Chemotherapy in a Patient With a Malignant Glioneuronal Tumor and Underlying Ataxia Telangiectasia: A Case Report and Review of the Literature
Authors: Mariko D. DeWire, Chris Beltran, Frederick A. Boop, Kathleen J. Helton, David W. Ellison, Peter J. McKinnon, Amar Gajjar, Atmaram S. Pai Panandiker
Journal: Journal of Clinical Oncology (2012)
Compliance with drug treatment
Authors: K. Coonan, M I Drury
Journal: BMJ (1979)

in water and ethanol, insoluble in chloroform and ether, stable at pH 6 8, and moderately stable to heat.'He also consulted a number of colleagues in 1929 and subsequently about how to proceed with extraction.Two of them, Stuart Craddock and Frederick Ridley, evaporated extracts in vacuo without success.Fleming then consulted several chemists independently, including Harold King, head of the Medical Research Council's laboratory at Hampstead, who told me later that they "had not been able to do much work on penicillin."Harold Raistrick, professor of biochemistry at the London School of Hygiene, worked harder on the problem collaboratively with R Lovell and P W Clutterbuck, but they were equally unsuccessful.2I have in my possession a bottle of dried yellow pigment purified by Raistrick from the crude brew in 1930 and given to me later by one of his assistants.When tested many years ago it contained none of the stable degradation products of penicillin.From 1932 onward, there are no records of further attempts to extract any active principles from the penicillin mould or the crude brew.In retrospect, it is very surprising that bacteriologists of the time ignored his findings, for filtrates of crude brew killed staphylococci and other organisms at dilutions of 1600, were non-toxic to leucocytes, and apparently eliminated sensitive organisms from burns, wounds, and ocular and other localised infections.3Until 1936 Fleming continued to draw attention to these unique properties but no one in the domestic research councils or pharmaceutical industry, or internationally, evinced any interest.4My reading of the record' and my acquaintance (later) with Fleming himself leave me convinced that he did not surrender easily to Wright or anyone else, but that he was by 1936 at his wit's end.So he followed the only course open to an honest scientist by describing his findings in a manner which left open the track, accurately, for the subsequent discovery of the active principle at Oxford a few years later by Chain, Florey, and their colleagues.
Doctors on hunger strike in Bombay
Authors: G. Mudur
Journal: BMJ (1996)

Six hospital doctors in Bombay are on an indefinite hunger strike in protest at poor pay and conditions of service. Resident doctors in government hospitals across Maharashtra state (of which Bombay is the capital city) have withdrawn their labour for over a month and announced this week that their strike would continue but that they would consider “written proposals” from the government. The strike by some 4500 resident doctors has crippled services in more than 30 hospitals in the state. With only senior doctors working, hospitals have turned away thousands of patients, postponed operations, and …
Percutaneous Transhepatic Sphincterotomy - A Report on 3 Cases
Authors: E. Zanon, D. Righi, U. Maisano, D. Regge, A. Ferrari, S. Recchia, G. Gandini
Journal: Endoscopy (1991)

The technique of percutaneous transhepatic sphincterotomy is described. This procedure was employed in 3 patients with common bile duct (CBD) stones in whom a previous attempted endoscopic procedure had failed for anatomical reasons (a Billroth II gastric resection or a partial gastric resection with Braun anastomosis). Complete immediate success was obtained in all 3 patients. Furthermore, no major complications occurred during transhepatic treatment. The authors suggest that PTS be employed electively in patients with diseases of the biliary tree in whom the endoscopic approach fails.
A SPLINT TO PREVENT CONTRACTURE IN SURGERY OF THE HAND
Authors: E. L. Gage
Journal: JAMA (1930)

The splints commonly used to prevent digital contracture, namely, molded plaster-of-paris splints and banjo finger extension splints, have proved unsatisfactory when combined with wet dressings or the hand bath. The molded plaster splints crumble, and the adhesive tape finger extensions of the banjo splints become loosened and useless as the result of the moisture. Metal splints which can be combined with wet dressings have the disadvantage of obscuring x-rays. So much hand surgery is done in the presence of existing or potential infection that a splint, that will prevent contracture of the fingers as well as permit the coincident use of wet dressings and x-rays is desirable. The splint shown in the accompanying illustration was devised for a powder wound of the right palm. A boy, aged 13, had discharged a blank cartridge into the palm of his right hand. At operation the powder was found disseminated throughout the palmar
Estrogen plus progestin increased long-term risk for invasive breast cancer in postmenopausal women
Authors: Robert P. Kauffman
Journal: Annals of Internal Medicine (2011)

Source Citation Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010;304:1684-92. 20959578
Novel Cardiac Troponin T Mutation as a Cause of Familial Dilated Cardiomyopathy
Authors: Duanxiang Li, Grazyna Z. Czernuszewicz, Oscar Gonzalez, Terry Tapscott, Akihiko Karibe, Jean-Bernard Durand, Ramon Brugada, Rita Hill, Jane M. Gregoritch, Jeffrey L. Anderson, Miguel Quiñones, Linda L. Bachinski, Robert Roberts
Journal: Circulation (2001)

Background Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomyopathy (FHCM) are the 2 most common forms of primary cardiac muscle diseases. Studies indicate that mutations in sarcomeric proteins are responsible for FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evidence is evolving, however, that such conclusions are premature. Methods and Results A novel missense mutation in the cardiac troponin T gene was identified by direct sequencing and confirmed by endonuclease restriction analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alters the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not found in 100 normal control subjects. Clinical features were congestive heart failure with premature deaths. The age of onset and severity of the disease are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation. Conclusions Thus, the novel cardiac troponin T mutation Arg141Trp is responsible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phenotype, whether it be hypertrophy or dilatation, is determined by the specific mutation rather than the gene.
Monitoring of assisted reproduction techniques is inadequate, US experts say
Authors: C. Marwick
Journal: BMJ (2003)

US doctors expressed concern last week that no system existed for monitoring children born through the use of assisted reproduction technologies, such as in vitro fertilisation, artificial insemination, interfallopian transfer, and intracytoplasmic sperm injection. They were also concerned about the lack of a system for ensuring that the embryonic and fetal genetic tests during such pregnancies were being done accurately.

“We do not have an effective system for monitoring the health, development, and outcomes of these children,” said Dr Kathy Hudson, director of the genetics and public policy centre at Johns Hopkins University. Dr Hudson was speaking at a meeting of the President's Council on Bioethics. …
The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer.
Authors: B Ketterer, J M Harris, G Talaska, D J Meyer, S E Pemble, J B Taylor, N P Lang, F F Kadlubar
Journal: Environmental Health Perspectives (1992)

Cytosolic glutathione S-transferases (GSTs) are a supergene family of dimeric enzymes capable of detoxifying a number of carcinogenic electrophiles. Of the numerous components of tobacco smoke, the polycyclic aromatic hydrocarbons appear to be the principal compounds that yield substrates for these enzymes, GSTM1-1 being effective with those PAH derivatives so far studied; however, the gene locus for GSTM1 is polymorphic, containing two well-characterized expressing genes and a null allele. Use of cDNA for GSTM1-1 or appropriate fragments of genomic clones as probes in Southern blots indicated that the null allele is due to the absence of GSTM1. In preliminary experiments, described here, with lung tissue from smokers, levels of 32P-postlabeled nuclease P1-enhanced DNA adducts were inversely correlated with levels of antigen cross-reacting with antibody to GSTM1-1, suggesting that initiation depends on the expression of GSTM1-1. Since similar quantities of DNA adducts and GSTM1-1 activity have been shown to occur in bronchial and peripheral lung, however, the development of malignancy, which is usually in the bronchial region, presumably depends on additional factors that bring about promotion and progression, which are not necessarily affected by GSTM1 expression. Two epidemiological studies have been carried out in which a possible correlation between the absence of GSTM1 and lung cancer incidence is considered. In the first, involving a U.S. population sample, smokers with and without lung cancer were phenotyped, and a highly significant correlation between the absence of GSTM1-1 activity and adenocarcinoma of the lung was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Choosing among Partition Models in Bayesian Phylogenetics
Authors: Y. Fan, R. Wu, M.-H. Chen, L. Kuo, P. O. Lewis
Journal: Molecular Biology and Evolution (2010)

Bayesian phylogenetic analyses often depend on Bayes factors (BFs) to determine the optimal way to partition the data. The marginal likelihoods used to compute BFs, in turn, are most commonly estimated using the harmonic mean (HM) method, which has been shown to be inaccurate. We describe a new more accurate method for estimating the marginal likelihood of a model and compare it with the HM method on both simulated and empirical data. The new method generalizes our previously described stepping-stone (SS) approach by making use of a reference distribution parameterized using samples from the posterior distribution. This avoids one challenging aspect of the original SS method, namely the need to sample from distributions that are close (in the Kullback–Leibler sense) to the prior. We specifically address the choice of partition models and find that using the HM method can lead to a strong preference for an overpartitioned model. In contrast to the HM method and the original SS method, we show using simulated data that the generalized SS method is strikingly more precise (repeatable BF values of the same data and partition model) and yields BF values that are much more reasonable than those produced by the HM method. Comparisons of HM and generalized SS methods on an empirical data set demonstrate that the generalized SS method tends to choose simpler partition schemes that are more in line with expectation based on inferred patterns of molecular evolution. The generalized SS method shares with thermodynamic integration the need to sample from a series of distributions in addition to the posterior. Such dedicated path-based Markov chain Monte Carlo analyses appear to be a cost of estimating marginal likelihoods accurately.
Antihypertensive and Water and Sodium Balance Effects of Felodipine, A New Vasodilating Calcium Antagonist, in Hypertensive Patients
Authors: G. Leonetti, M. Fruscio, L. Terzoli, L. Rupoli, R. Gradnik, L. Sampieri, C. Cuspidi, L. Boselli, G. Bolla, A. Zanchetti
Journal: Drugs (1985)
Ethics and Public Health Emergencies: Rationing Vaccines
Authors: Matthew K. Wynia
Journal: The American Journal of Bioethics (2006)

There are three broad ethical issues related to handling public health emergencies. They are the three R's-rationing, restrictions and responsibilities. Recently, a severe shortage of annual influenza vaccine in the US, combined with the threat of pandemic flu, has provided an opportunity for policy makers to think about rationing in very concrete terms. Some lessons from annual flu vaccination likely will apply to pandemic vaccine distribution, but many preparatory decisions must be based on very rough estimates. What ethical principles should guide rationing decisions, what data should inform these decisions, how to revise decisions as new data emerge, and how to implement rationing decisions on the ground are all important considerations. In addition, ethicists might be able to help policy makers think through the importance of international cooperation in surmounting global rationing dilemmas and to accept the inevitable responsibilities of government in making and implementing rationing decisions.
Re: Salvatore Siracusano, Francesca Vita, Rita Abbate, Stefano Ciciliato, Violetta Borelli, Massimiliano Bernabei and Giuliano Zabucchi. The Role of Granulocytes Following Intravesical BCG Prophylaxis. Eur Urol 2007;51:1589–99
Authors: Sven Brandau, Henrik Suttmann
Journal: European Urology (2007)
Do Nonsteroidal Anti-inflammatory Drugs Affect Blood Pressure? A Meta-Analysis
Authors: Anthony G. Johnson
Journal: Annals of Internal Medicine (1994)

A meta-analysis of randomized trials studying the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure.Eight databases were searched, yielding 38 randomized, placebo-controlled trials and 12 randomized but not placebo-controlled trials (comparing two or more NSAIDs).Pooled mean treatment effects were computed in each trial for blood pressure, weight, creatinine clearance, plasma renin activity, and daily urinary excretion of sodium and prostaglandins. Meta-analyses of these variables were done for all randomized, controlled trials; for all randomized, uncontrolled trials; and for several subgroups.When pooled, NSAIDs elevated supine mean blood pressure by 5.0 mm Hg (95% CI, 1.2 to 8.7 mm Hg) but had no effect on variables other than blood pressure. Nonsteroidal anti-inflammatory drugs antagonized the antihypertensive effect of beta-blockers (blood pressure elevation, 6.2 mm Hg; CI, 1.1 to 11.4 mm Hg) more than did vasodilators and diuretics. Among NSAIDs, piroxicam produced the most marked elevation in blood pressure (6.2 mm Hg; CI, 0.8 to 11.5 mm Hg), whereas sulindac and aspirin had the least hypertensive effect.Nonsteroidal anti-inflammatory drugs may elevate blood pressure and antagonize the blood pressure-lowering effect of antihypertensive medication to an extent that may potentially increase hypertension-related morbidity. Although certain NSAIDs and antihypertensive agents could be more likely to produce these effects, the underlying mechanisms require further study.
Pulmonary Mucormycosis in Acute Histiocytic Leukemia
Authors: Mario Stefanini, Salvatore Allegra
Journal: New England Journal of Medicine (1957)

THE introduction of antibiotics, chemotherapeutic agents, ACTH and steroid hormones has greatly altered the natural course of the acute leukemias. Temporary remissions are more frequently obtained; at the same time new complications arise that may be related to the prolonged survival of the patient or to the very effect of medication.The present article describes a case of acute histiocytic leukemia treated with ACTH, prednisone and antibiotics whose course was complicated terminally by pulmonary mucormycosis. Although many species of the family mucoraceae are common laboratory contaminants, the genus rhizopus may be pathogenic for man. Cerebral manifestations are encountered most often. . . .
Adjuvant Influenza Adenovirus Vaccine
Authors: Gordon Meiklejohn
Journal: JAMA (1962)

Vaccine containing 4 influenza A, 2 influenza B, and 2 adenovirus strains, emulsified in mineral oil-arlacel adjuvant, was given to 2,303 men. A control solution was given to 2,256 men in the same military units. Antibody response to influenza A 2 and adenovirus Type 7 was of a high order. No undesirable reactions to the vaccine were noted. Illnesses of hospitalized men were classified by results of appropriate serologic tests. Outbreaks of influenza A 2 and adenovirus Type 7 occurred. In the control group there were 35 cases of influenza, 40 of adenovirus infections, and 3 of both influenza and adenovirus. In the vaccinated group there were 2 cases of influenza and 4 of adenovirus infection. Other respiratory diseases occurred with comparable frequency in vaccinated and control groups. The protection ratio for influenza A 2 was approximately 94% and for adenovirus, 90%.
Enhanced biliary iron excretion with amphiphilic diethylenetriaminepentaacetic acid
Authors: Paul C. Adams, Edward Lin, Kathryn R. Barber, Chris W. M. Grant
Journal: Hepatology (1991)

The elimination of toxic metal ions metabolically accumulated by patients remains a difficult clinical problem and a target of drug development. DTPA (diethylenetriaminepentaacetic acid) is a hydrophilic chelating agent with high affinity for divalent and trivalent metal ions including iron but with a limited ability to cross cell membranes for access to iron stores. In this study we have synthesized an amphiphilic form of this chelator–DTPA covalently linked to the phospholipid phosphatidylethanolamine (PE)–to produce a chelator that incorporates completely and stably into liposome membranes for efficient delivery to the liver and reticuloendothelial system. Biliary and urinary excretion of iron were studied in iron-loaded rats (n = 15) in association with a 2-hr intravenous infusion of sonicated liposomes of 1:1 amphiphilic phosphatidylethanolamine-DTPA/egg phosphatidylcholine (L-PE-DTPA) and compared with excretion obtained using equivalent amounts of watersoluble DTPA (alone or mixed with egg phosphatidylcholine liposomes [L-DTPA] as controls). For a 6-hr period, the administration of L-PE-DTPA resulted in approximately a 20-fold increase in biliary iron excretion (480 ± 160 μg/6 hr, mean ± S.D.) compared with that seen with DTPA (21.2 ± 4.0μg/6 hr) and L-DTPA (23.1 ± 5.0 μg/6 hr) (p < 0.05, analysis of variance). Urinary iron excretion was significantly decreased with L-PE-DTPA (41.5 ± 38 μg/6hr) compared with DTPA (154 ± 110 μg/6 hr) and L-DTPA (86 ± 17 μg/6 hr) (p < 0.05). Combined biliary and urinary excretion of iron was three to four times greater with L-PE-DTPA. This study suggests that the use of a highly water-insoluble amphiphilic form of DTPA as sonicated liposomes altered the route and extent of delivery of the chelator to the iron stores, resulting in a significant increase in biliary iron excretion. (HEPATOLOGY 1991;14:1230–1234.)
SCINTIGRAPHIC METHODS FOR THE DETECTION AND LOCALIZATION OF GASTROINTESTINAL HEMORRHAGE
Authors: Stephen R. Bunker, Robert J. Lull, Robert J. McAuley, Jerry M. Brown, Robert S. Hattner, Robert J. Telepak, Michael F. Hartshorne, John H. Jackson, John P. Huberty
Journal: Clinical Nuclear Medicine (1982)

The Nuclear Medicine Center and the Department of Radiology, The University of Texas Health Science Center at Dallas, Dallas, TX