tbuckley/cabot-search huggingface dataset:
Abstract LB-1: Discovery and optimization of orally bioavailable, selective and potent ATP-independent Akt inhibitors
Authors: Thomas C.K. Chan, Mark A. Ashwell, Jean-Marc Lapierre, Christopher Brassard, Cathy Bull, Susan Cornell-Kennon, Sudharshan Eathiraj, Dennis S. France, Jason Hill, Steffi Koerner, Eoin Kelleher, Darin Kizer, Yanbin Liu, Jeff Link, Sapna Makhija, Magdi Moussa, Nivedita Namdev, Robert Nicewonger, Uma Uppalapati, Rocio Palma, Jeff Szwaya, Manish Tandon, David Vensel, Laurie Volak, Erika Volckova, Neil Westland, Hui Wu, Rui-Yang Yang
Journal: Cancer Research (2012)

Abstract Herein we describe the implementation of a biochemical and biophysical screening strategy to discover small molecules that inhibit Akt through a mechanism distinct from ATP-competitive inhibitors. A series of novel derivatives of the core scaffold 3H-imidazo[4,5-b]pyridine were identified and optimized. These Akt inhibitors demonstrated potent inhibition of intracellular Akt and downstream targets including PRAS40 activation in vitro. Pharmacodynamic and pharmacokinetic studies in vivo demonstrated the effectiveness of the series at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice. Co-crystallization studies with un-phosphorylated Akt1 revealed that as a consequence of binding these novel, potent and selective, ATP-independent inhibitors the ATP binding cleft is occupied by non-polar residues which are associated as tight clusters. The cleft is closed with a ‘hydrophobic lock’ which may function to sterically exclude the binding of both ATP and ATP-competitive inhibitors. 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 LB-1. doi:1538-7445.AM2012-LB-1
P814 INCREASED SERUM LEVEL OF HEAT SHOCK PROTEIN 27 IS ASSOCIATED WITH LOW RISK OF CORONARY ARTERY DISEASE (CAD) IN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Authors: E. Elsheikh, Z. Younoszai, M. Otgonsuren, E. Younossi, B. Lam, T. Jeffers, S. Frost, B. Raybuck, Z.M. Younossi
Journal: Journal of Hepatology (2014)
ABC of arterial and venous disease: Varicose veins
Authors: N. J M London
Journal: BMJ (2000)

Varicose veins are tortuous, twisted, or lengthened veins. Unless the enlargement is severe, size alone does not indicate abnormality because size can vary depending on ambient temperature and, in women, hormonal factors. In addition, normal superficial veins in a thin person may appear large, whereas varicose veins in an obese person may be hidden. Varicose veins can be classified as trunk, reticular, or telangiectasia. Telangiectasia are also referred to as spider veins, star bursts, thread veins, or matted veins. Most varicose veins are primary; only the minority are secondary to conditions such as deep vein thrombosis and occlusion, pelvic tumours, or arteriovenous fistulae.
Soluble Transforming Growth Factor- β Type III Receptor Gene Transfection Inhibits Fibrous Airway Obliteration in a Rat Model of Bronchiolitis Obliterans
Authors: MINGYAO LIU, MICHIHARU SUGA, ALEXANDRA A. MacLEAN, JUDITH A. ST. GEORGE, DAVID W. SOUZA, SHAF KESHAVJEE
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor- β (TGF β ) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGF β staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGF β receptor type III (TGFBIIIR), by blocking TGF β binding to its membrane receptors, functions as a TGF β antagonist. To study the role of TGF β in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 × 109 particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGF β expressed in the allografts play a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGF β activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.
Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia
Authors: M van Gelder, L C de Wreede, J Schetelig, A van Biezen, L Volin, J Maertens, M Robin, E Petersen, T de Witte, N Kröger
Journal: Leukemia (2012)
Diabetic Cardiomyopathy Revisited
Authors: Sihem Boudina, E. Dale Abel
Journal: Circulation (2007)

Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. This review discusses the latest findings in diabetic humans and in animal models and reviews emerging new mechanisms that may be involved in the development and progression of cardiac dysfunction in diabetes.
Alcohol and Oxidative Liver Injury
Authors: Aparajita Dey, Arthur I. Cederbaum
Journal: Hepatology (2006)

Acute and chronic ethanol treatment has been shown to increase the production of reactive oxygen species, lower cellular antioxidant levels, and enhance oxidative stress in many tissues, especially the liver. Ethanol-induced oxidative stress plays a major role in the mechanisms by which ethanol produces liver injury. Many pathways play a key role in how ethanol induces oxidative stress. This review summarizes some of the leading pathways and discusses the evidence for their contribution to alcohol-induced liver injury. Many of the seminal reports in this topic have been published in Hepatology, and it is fitting to review this research area for the 25th Anniversary Issue of the Journal. (Hepatology 2006;43: S63-S74.)
Abstract 3311: Glycosylation alterations associated with pancreatic cancer EMT probed using gene expression in three model systems
Authors: Kevin Maupin, Arkadeep Sinha, Jeremy Miller, Juli Ross, Vincent Paulino, Venkat Keshamouni, Nhan Tran, Michael Berens, Craig Webb, Brian B. Haab
Journal: Cancer Research (2010)

Abstract The lethal nature of pancreatic cancer is related to its propensity to disseminate at early stages and its resistance to chemotherapeutics. Cancer cells that have undergone epithelial-mesenchymal transition acquire these traits and may play an important role in pancreatic cancer progression. The identification of the defining molecular features and functional drivers of pancreatic cancer EMT may lead to new methods to control cancer progression. Particular glycosylation patterns are specifically associated with cellular differentiation and activation and play functional roles in cell migration and signal transduction. Therefore we hypothesized that pancreatic cancer EMT is characterized by specific glycosylation alterations that play functional roles in cancer cell differentiation or migration. As a first step toward investigating that hypothesis, we characterized the expression of glycan-related genes in three model systems of pancreatic cancer EMT. We used whole-genome microarrays to study gene expression in: 1) TGF-beta-induced EMT in two different cell lines; 2) a panel of 23 pancreatic cancer cell lines characterized as either epithelial-like or mesenchymal-like; and 3) actively-migrating and stationary cells from two different cell lines. We compiled a list of 585 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc.) or EMT. Using this list, we found that each model system displayed both elevations and reductions with high significance in multiple glycan-related genes. The percentage of glycan-related genes showing changes exceeded the percentage of overall genes showing changes in each case, suggesting an important role of glycan alterations in EMT. To narrow the list of candidate genes for further study, we looked at the overlap in altered genes between the model systems. ST6GALNAC4, an enzyme that transfers sialic acid to particular presentations of the N-acetyl galactosamine monosaccharide, was elevated in the pancreatic cancer cell lines of all model systems. Glycan structures similar to those synthesized by ST6GALNAC4 are commonly associated with cancer. Genes involved in the sulfation and de-sulfation of glycosaminoglycans were frequently altered, as well as members of the mannose receptor family, each of which suggests routes of modulating extracellular interactions. These results support the involvement of glycan alterations in cancer EMT and suggest targets for the further study of mechanistic drivers of pancreatic cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3311.
1070-129 Elderly acute coronary syndrome patients were undertreated with worse one-year outcome: Findings from a contemporary registry
Authors: Raymond T Yan, Andrew T Yan, Mary Tan, Chi-Ming Chow, David H Fitchett, Frank L Ervin, Heather Martin, James Y Cha, Anatoly Langer, Shaun G Goodman
Journal: Journal of the American College of Cardiology (2004)
Retrograde Fallopian Tube Transport
Authors: Carl J. Pauerstein
Journal: JAMA (1985)

Dr Schwartz and colleagues<sup>1</sup>have reported vernix caseosa peritonitis after premature rupture of the membranes during the 25th week of pregnancy. They postulate that the vernix was delivered to the peritoneal cavity via retrograde transport through the fallopian tubes. The concept of retrograde transport through the fallopian tubes is not new. Various investigations dating back to 1880 have demonstrated that small particles such as india ink, carbon, starch, and talc can be transported through the oviduct in both directions at all times in the estrus or menstrual cycle.<sup>2</sup>In performing its normal physiological function, the oviduct must transport the sperm toward the ovary and the ovum toward the uterus. Although the mechanism of the transport of sperm from the uterus to the fimbriated end of the oviduct is not clearly defined, Eddy et al<sup>3</sup>clearly demonstrated that in the rabbit oviduct, cilia are not essential to the
High uptake of HPV immunisation in Scotland – perspectives on maximising uptake
Authors: A Potts, K Sinka, J Love, R Gordon, S McLean, W Malcolm, D Ross, M Donaghy
Journal: Eurosurveillance (2013)

In September 2008, Scotland introduced a national human papillomavirus (HPV) immunisation programme with bivalent HPV vaccine, to prevent cervical cancer. This school-based programme routinely vaccinates girls aged between 12 and 13 years. A catch-up campaign, running over three years, also began at this time, offering vaccination to all girls aged 13 years to under 18 years old. The HPV immunisation campaign presented challenges due to this vaccine being targeted to girls in school and older girls who had left school. Following a long and comprehensive planning process, this campaign was successfully implemented across Scotland, delivering high vaccine uptake of 91.4% for three doses of vaccine in the first year (September 2008 to August 2009) for the routine cohort and 90.1% in the second year (September 2009 to August 2010) for the routine cohort. We describe the planning process, challenges and implementation strategies employed to achieve this high uptake.
RATE OF HEMOGLOBIN REGENERATION IN BLOOD DONORS
Authors: WILLIS M. FOWLER
Journal: JAMA (1942)

During the past twenty years there has been a great increase in the number of blood transfusions administered, and the recent use of normal and lyophilized serum in combating shock and in restoring the plasma proteins to their normal level promises to increase still further the already great demand for blood. In spite of the frequent use of whole blood and blood serum there have been surprisingly few studies on the rate of hemoglobin regeneration in the blood donors. Most of the recorded observations have been made on groups of professional donors who have given varying amounts of blood over a period of months or years, and the reports have been concerned with the hemoglobin and erythrocyte levels after multiple donations. Giffin and Haines<sup>1</sup>studied 84 donors, many of whom had given blood for 20 or more transfusions, and concluded that donations of 500 cc. of blood at intervals
Effects of a molecular change in collagen on lung structure and mechanical function.
Authors: N N Stanley, R Alper, E L Cunningham, N S Cherniack, N A Kefalides
Journal: Journal of Clinical Investigation (1975)

Semicarbazide, a lathyrogen, was given to growing rats to elucidate the consequences of altering the molecular structure of fibrous proteins within the lung. Static pressure-volume (P-V) measurements during deflation of saline-filled lungs showed normal recoil pressure and compliance values within the physiological range of lung volume. Quasi-static P-V measurements were also normal during slow reinflation, even beyond physiological limits to a recoil pressure of 20 cm H20. However, the lungs of experimental rats ruptured at much lower recoil pressures than controls. Histology was normal in lungs fixed at 20 cm H20. In contrast, lungs showed dilation of terminal air spaces, rupture of alveolar walls, and an increase in mean linear intercept in experimental compared with control specimens, when fixed at 30 cm H20. Biochemical analyses revealed reduced cross-linking of lung collagen without change in its total content. There were no detectable changes in the quantity or quality of lung elastin. It is concluded that semicarbazide may selectively impair the maturation of lung collagen and that immaturity of lung collagen is associated with a reduction in the tensile strength of lung tissue, without changes in elasticity within physiological volume limits.
Rapid Evolution of a Cyclin A Inhibitor Gene, roughex, in Drosophila
Authors: Sergei N. Avedisov, Igor B. Rogozin, Eugene V. Koonin, Barbara J. Thomas
Journal: Molecular Biology and Evolution (2001)

The recent sequencing of the complete genome of the fruit fly Drosophila melanogaster has yielded about 30% of the predicted genes with no obvious counterparts in other organisms. These rapidly evolving genes remain largely unexplored. Here, we present evidence for a striking variability in an important Drosophila cell cycle regulator encoded by the gene roughex (rux) in closely related fly species. The unusual level of Rux protein variability indicates that there are very low overall constraints on amino acid substitutions. Despite the lack of sequence similarity, certain common features, including the presence of a C-terminal nuclear localization signal and a functionally important N-terminal RXL cyclin-binding motif, exist between Rux and cyclin-dependent kinase inhibitors of the Cip/Kip family. These results indicate that even some genes involved in key regulatory processes in eukaryotes evolve at extremely high rates.
TCT-753 Efficacy and Feasibility of On-pump Transcatheter Aortic Valve Implantation in Patients with Severely Decompensated Heart Failure
Authors: Koichi Maeda, Toru Kuratani, Kei Torikai, Isama Mizote, Yasuhiro Ichibori, Satoshi Nakatani, Yasushi Sakata, Koichi Toda, Yoshiki Sawa
Journal: Journal of the American College of Cardiology (2014)
Targeting DNA Repair in Chronic Lymphocytic Leukemia Cells with a Novel Acyclic Nucleotide Analogue, GS-9219
Authors: Cheng-Yu Tsai, Adrian S. Ray, Daniel B. Tumas, Michael J. Keating, Hans Reiser, William Plunkett
Journal: Clinical Cancer Research (2009)

GS-9219 is a cell-permeable prodrug of the acyclic nucleotide analogue 9-(2-phosphonylmethoxyethyl)guanine (PMEG); the incorporation of the active metabolite PMEG diphosphate (PMEGpp) into DNA results in DNA chain termination due to the lack of a 3'-hydroxyl moiety. We hypothesized that the incorporation of PMEGpp into DNA during repair resynthesis would result in the inhibition of DNA repair and the accumulation of DNA breaks in chronic lymphocytic leukemia (CLL) cells that would activate signaling pathways to cell death.To test this hypothesis, CLL cells were irradiated with UV light to stimulate nucleotide excision repair pathways, enabling the incorporation of PMEGpp into DNA. The combination effects of GS-9219 and DNA-damaging agents and the signaling mechanisms activated in response to DNA repair inhibition by GS-9219, as well as changes in CLL cell viability, were investigated.PMEGpp was incorporated into DNA in CLL cells when nucleotide excision repair was activated by UV. Following PMEGpp incorporation, DNA repair was inhibited, which led to the accumulation of DNA strand breaks. The presence of DNA strand breaks activated the phosphatidylinositol 3-kinase-like protein kinase family members ataxia-telangiectasia mutated and DNA-dependent protein kinase. P53 was phosphorylated and stabilized in response to the inhibition of DNA repair. P53 targeted proteins, Puma and Bax, were up-regulated and activated. The combination of GS-9219 and DNA-damaging agents resulted in more cell death than the sum of the single agents alone.GS-9219 inhibits DNA repair in CLL cells, an action that stimulates signaling pathways for apoptosis induction.
Lung angiotensin converting enzyme activity in rats with pulmonary hypertension.
Authors: P M Keane, J M Kay, K L Suyama, D Gauthier, K Andrew
Journal: Thorax (1982)

We have studied serum and lung tissue angiotensin converting enzyme (ACE) activity in female Wistar rats with pulmonary hypertension induced by two different methods. Chronic pulmonary hypertension was produced in one group of 10 rats (CH) by confinement in a hypobaric chamber (380 mmHg) for three weeks, and in another group fo 10 rats (M) by a single subcutaneous injection of monocrotaline (60 mg/kg body weight). In these two groups of tests rats and in 20 untreated controls (C), we evaluated right ventricular mean systolic blood pressure (Prvs mmHg), right ventricular hypertrophy, and serum ACE (n mol/ml/min). In lung tissue homogenate, we measured the specific activity of ACE (n mol/mg protein/min), alkaline phosphatase (AP) (IU/mg protein) and lactic dehydrogenase (LDH) (IU/mg protein). The Prvs in groups, C, CH, and M was 25 +/- 7 SD, 41 +/- 7, and 51 +/- 5, respectively. The ratio of right ot left ventricular weight (RV/(LV + S)%) in groups, C, CH, and M was 29 +/- 4, 52 +/- 5, and 56 +/- 7, respectively. The lung tissue ACE in groups C, CH, and M was 85 +/- 11, 65 +/- 20, and 22 +/- 5, respectively. In groups CH, and M the Prvs and RV/(LV + S)% were significantly elevated above control values while lung ACE was significant decreased (p less than 0.05). There was a significant inverse relationship between lung ACE on one hand, and Prvs (r = - 0.73) and RV/(LV + S)% (r = - 0.71) on the other hand. Serum ACE and lung AP were unchanged. In group M there was a slight but significant reduction in lung LDH. Chronic pulmonary hypertension, irrespective of its method of production, is associated with decreased lung ACE. The reduction in lung ACE is inversely proportional to the severity of pulmonary hypertension and right ventricular hypertrophy.
miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1
Authors: Marek Mraz, Liguang Chen, Laura Z. Rassenti, Emanuela M. Ghia, Hongying Li, Kristen Jepsen, Erin N. Smith, Karen Messer, Kelly A. Frazer, Thomas J. Kipps
Journal: Blood (2014)
Interaction With Myd88-dependent CD8-CD11c+ Cells Mediates Rapid Induction Of Antigen-specific IgE-suppressive Gamma Delta T Cells
Authors: Y. Huang, M.K. MacCLeod, A.S. McKee, M.K. Aydintug, C.V. Jacubzick, R.M. Kedl, D. Sun, R.L. O'Brien, W.K. Born
Journal: Journal of Allergy and Clinical Immunology (2012)
A Historical Note on Placebo Effects in Vomiting of Pregnancy
Authors: L. Chertok
Journal: JAMA (1965)

To the Editor:—  In recent years there have been numerous studies of placebo effects (double: and tripleblind tests, etc) but it is interesting to draw attention to some cases of spontaneous placebo effects which are to be found in the history of the vomiting of pregnancy and its treatment.  The history of therapy for vomiting is a long story. All kinds of treatments have been tried, from ecrevisse a la bordelaise to electric shock, through the whole pharmacopeia, the best vineyards in France, and the various gastronomic specialties. Among these treatments, some have been quite famous. On June 9, 1874, an English doctor, Copeman, who was then president of the British Medical Association and an authority on obstetrics, was called into consultation by a colleague in the case of a pregnant woman, 35 years of age, afflicted with intractable vomiting. The state of this woman was such that it was