tbuckley/cabot-search huggingface dataset:
Abstract 1635: Discovery of novel SMAC mimetics as selective IAP inhibitors
Authors: Jin Wang, Wei Li
Journal: Cancer Research (2014)

Abstract Inhibitor of apoptosis (IAP) proteins are widely considered as promising cancer drug targets, especially for drug-resistant tumors. Mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (SMAC) is a rational strategy to design potential IAP inhibitors. In this report, we used the bioactive conformation of AVPI tetrapeptide in the N-terminus of SMAC as a template and performed a shape-based virtual screening against a drug-like compound library to identify novel IAP inhibitors. Top hits were subsequently docked to available IAP crystal structures as a secondary screening followed by validation using in vitro biological assays. Four novel hit compounds were identified to potently inhibit cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines. The best compound, UC-112, has IC50 values ranging from 0.7 to 3.4 µM. UC-112 also potently inhibits the growth of P-glycoprotein (P-gp) overexpressed multidrug-resistant cancer cells, strongly activates capase-3/7 and caspase-9 activities, and selectively down-regulates survivin level at a concentration as low as 1 µM. Co-incubation of UC-112 with a known proteasome inhibitor (MG132) rescued survivin inhibition, consistent with the anticipated mechanism of action for UC-112. As a single agent, UC-112 strongly inhibits tumor growth and reduces both XIAP and survivin levels in an A375 human melanoma xenograft model. Overall, our study identified novel scaffolds, especially UC-112, as new platforms on which potent and selective IAP antagonists can be developed. Citation Format: Jin Wang, Wei Li. Discovery of novel SMAC mimetics as selective IAP 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 1635. doi:10.1158/1538-7445.AM2014-1635
C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks - final results of the I.M.P.A.C.T.2 study
Authors: T. J. Craig, A. K. Bewtra, S. L. Bahna, D. Hurewitz, L. C. Schneider, R. J. Levy, J. N. Moy, J. Offenberger, K. W. Jacobson, W. H. Yang, F. Eidelman, G. Janss, F. R. Packer, M. A. Rojavin, T. Machnig, H.-O. Keinecke, R. L. Wasserman
Journal: Allergy (2011)

To cite this article: Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke H-O, Wasserman RL. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study. Allergy 2011; 66: 1604–1611. Abstract Background: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. Methods: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. Results: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10–53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39–0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8–26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. Conclusions: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location. See Special Feature Page for this article here
Medicine based evidence, a prerequisite for evidence based
Authors: J A Knottnerus, G J Dinant
Journal: BMJ (1997)

Seeking an evidence base for medicine is as old as medicine itself, but in the past decade the concept of evidence based medicine has done a good job in focusing explicit attention on the application of evidence from valid clinical research to clinical practice.1 2 Although current clinical practice is often evidence based,3 4 there is still much to be gained. Important new evidence from research often takes a long time to be implemented in daily care, while established practices persist even if they have been proved to be ineffective or harmful.5 In the meantime, many clinicians struggle to apply the results of studies that do not seem that relevant to their daily practice.

Evidence based medicine has been defined as the “conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.”2 What can we learn from the limitations of current best evidence for the way that we design future studies?

We face the problem that criteria for internal and external validity (that is, clinical …
Brian O'Carroll
Authors: T. O'Carroll, J. O'Carroll
Journal: BMJ (2011)

Brian O’Carroll was born in Oxford on 2 March 1917 and qualified from St Bartholomew’s Hospital Medical School in 1941, where he won the Brackenbury surgery prize. In 1942 he married Mildred Jones, and they had two children. He served in the Royal Army Medical Corps as a major in Normandy, West Africa, and Italy. After demobilisation in 1947, he …
Abstract 17007: Does Age Modify Gender-based Differences in Clinical Outcomes Following Percutaneous Coronary Intervention (PCI)
Authors: Kleanthis Theodoropoulos, Jennifer Yu, Melisssa Aquino, Usman Baber, Swathi Roy, Jason Kovacic, Joseph Sweeny, Roxana Mehran, Samin Sharma, Annapoorna Kini
Journal: Circulation (2014)

Introduction: Women experience higher complication rates and mortality after PCI than men but it remains unknown whether these differences are sustained among younger and older patients. Hypothesis/Objectives: To investigate if previously reported gender-based disparities in outcome following percutaneous coronary intervention (PCI) are modified by age in a large and racially-diverse cohort in the drug eluting stent (DES) era. Methods: A total of 23,400 patients (7942 female, 34%) underwent PCI of de novo lesion(s) from 01/2005 to 12/2012 at Mount Sinai Hospital. We compared demographics, procedural characteristics, and 1-year rates of death, myocardial infarction, and major adverse cardiovascular events (MACE), by sex in younger (≤65 years old, n=11,381) and older (&gt;65 years old, n= 12,019) patients. Results: Regardless of age, compared to males, females had higher body mass index (BMI), better renal function, smoked less, but were more hypertensive and diabetic. Women had higher HDL and LDL cholesterol levels. More women presented with an unstable coronary syndrome and required left anterior descending artery PCI. Women had more vascular and bleeding complications post-PCI but the 30-day readmission rate did not differ between genders within age groups. At 1 year women, in both age categories, were at higher risk for death or myocardial infarction than men. Among younger patients, women had more MACE than men, but formal interaction testing was negative (Figure). Conclusion: Females undergoing PCI have more comorbidities and are at higher risk for unfavorable outcomes than males. The substantial gender-based differences in clinical outcomes following PCI were independent of age suggesting that preventive strategies should be promoted amongst women.
Medicare Drug Beneficiaries and Cost-Lowering Strategies
Authors: Nina H. Bjarnason, Jens P. Kampmann
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 13284: A Novel Formulation of Vasoactive Intestinal Peptide Attenuates both Acute Hypoxic Pulmonary Vasoconstriction and the Development of Pulmonary Hypertension
Authors: Dustin R Fraidenburg, Haiyang Tang, Abigail Drennan, Jason X Yuan
Journal: Circulation (2014)

Background: Vasoactive intestinal peptide (VIP) is an endogenous hormone that is known to relax vascular smooth muscle and has established anti-proliferative and immunomodulatory effects in the pulmonary circulation making it an attractive therapeutic target in pulmonary arterial hypertension (PAH). In the current study, a polymer-based nanocarrier (protected graft copolymer - PGC) formulation of VIP, which has been shown to increase the potency and duration of action of VIP, is used to show both acute vasodilatory effects and chronic therapeutic effects in experimental animal models of pulmonary hypertension. Methods: The isolated perfused mouse lung preparation is utilized to test acute hypoxic pulmonary vasoconstriction (HPV) in mice. Two animal models of pulmonary hypertension are used in preventative experiments, chronic hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. Right ventricular systolic pressure and Fulton’s index (weight ratio of RV/[LV+Septum]) are used for measures of pulmonary hemodynamics and RV hypertrophy respectively. Results: PGC-VIP decreased resting pulmonary artery pressure and attenuated acute HPV elicited by 1% inhaled oxygen tension in a dose dependent manner from 0.1 μM to 1.0 μM. After four weeks of chronic hypoxia, both RVSP measurements and Fulton’s index were significantly decreased in mice receiving 100 mg/kg intraperitoneal PGC-VIP every other day compared to vehicle control. Higher doses were associated with mortality in the treatment group. MCT-PH rats receiving subcutaneous PGC-VIP at a dose of 250 mg/kg failed to show improvement in RVSP or Fulton’s index compared to vehicle control. Conclusion: This novel formulation of VIP demonstrates both acute and chronic vasodilatory effects in the pulmonary circulation. Treatment with PGC-VIP can attenuate the development of hypoxic pulmonary hypertension, yet significant mortality is seen at higher doses. Subcutaneous injection failed to attenuate the development of experimental PH in rats, possibly due to an ineffective dose or route of administration. Further studies are underway to identify the ideal dosing strategy necessary to attenuate and potentially reverse experimental PH in animal models.
Reply to S. Zucker “The Swinging Pendulum of the Anemia of Cancer: Erythropoietin Trumps Hepcidin”
Authors: S. Hohaus, G. Leone, G. Massini, M. Giacheli, B. Vannata, L.M. Larocca, M.T. Voso, D.W. Swinkels
Journal: Journal of Clinical Oncology (2011)
Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques
Authors: Timothy W. Baba, Vladimir Liska, Anis H. Khimani, Nancy B. Ray, Peter J. Dailey, Dominique Penninck, Rod Bronson, Michael F. Greene, Harold M. McClure, Louis N. Martin, Ruth M. Ruprecht
Journal: Nature Medicine (1999)
New Method to Repair Faulty Genes Stirs Interest in Chimeraplasty TechniqueSwitch to Human Insulin Worries Some DiabeticsA Thought for Your PenniesNew Method to Repair Faulty Genes Stirs Interest in Chimeraplasty TechniqueSwitch to Human Insulin Worries Some DiabeticsA Thought for Your Pennies
Authors: J Stephenson
Journal: JAMA (1999)

Scientists have developed a provocative new technique for correcting tiny but potentially devastating errors in mutant genes, an approach they hope will someday provide a strategy for treating at least some genetic disorders.
Paraoxonase Variants Relate to 10-Year Risk in Coronary Artery Disease
Authors: Jakub J. Regieli, J. Wouter Jukema, Pieter A. Doevendans, Aeilko H. Zwinderman, John J. Kastelein, Diederick E. Grobbee, Yolanda van der Graaf
Journal: Journal of the American College of Cardiology (2009)
Cross‐reactions <i>vs</i> co‐sensitization evaluated by <i>in silico</i> motifs and <i>in vitro</i> IgE microarray testing
Authors: P. Pfiffner, B. M. Stadler, C. Rasi, E. Scala, A. Mari
Journal: Allergy (2011)

To cite this article: Pfiffner P, Stadler BM, Rasi C, Scala E, Mari A. Cross‐reactions vs co‐sensitization evaluated by in silico motifs and in vitro IgE microarray testing. Allergy 2012; 67 : 210–216. Abstract Background and objective: Using an in silico allergen clustering method, we have recently shown that allergen extracts are highly cross‐reactive. Here we used serological data from a multi‐array IgE test based on recombinant or highly purified natural allergens to evaluate whether co‐reactions are true cross‐reactions or co‐sensitizations by allergens with the same motifs. Methods: The serum database consisted of 3142 samples, each tested against 103 highly purified natural or recombinant allergens. Cross‐reactivity was predicted by an iterative motif‐finding algorithm through sequence motifs identified in 2708 known allergens. Results: Allergen proteins containing the same motifs cross‐reacted as predicted. However, proteins with identical motifs revealed a hierarchy in the degree of cross‐reaction: The more frequent an allergen was positive in the allergic population, the less frequently it was cross‐reacting and vice versa. Co‐sensitization was analyzed by splitting the dataset into patient groups that were most likely sensitized through geographical occurrence of allergens. Interestingly, most co‐reactions are cross‐reactions but not co‐sensitizations. Conclusions: The observed hierarchy of cross‐reactivity may play an important role for the future management of allergic diseases.
Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma
Authors: Christian D. Fingas, Joachim C. Mertens, Nataliya Razumilava, Svenja Sydor, Steven F. Bronk, John D. Christensen, Sumera I. Ilyas, Ali Canbay, Jürgen W. Treckmann, Andreas Paul, Alphonse E. Sirica, Gregory J. Gores
Journal: Hepatology (2013)

Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh-treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo.
Abstract P044: Alcohol Consumption, Statin Use and Risk of All-Cause Mortality in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort
Authors: Edmond K Kabagambe, James N Kiage, Suzanne E Judd, James C Slaughter, Loren Lipworth, Uchechukwu Sampson, Luc Djousse, Eric B Rimm, Mary Cushman, Sergio Fazio, Monika Safford, Virginia J Howard, George Howard
Journal: Circulation (2015)

Background:  Moderate alcohol consumption is associated with a lower risk of all-cause mortality while heavy alcohol intake increases this risk. Statins also reduce all-cause mortality. In recent years, use of statins has increased, resulting in frequent joint exposure to both alcohol and statins, but whether moderate alcohol consumption confers a mortality benefit beyond that from statin therapy is not known.   Methods:  We followed 23,555 black and white men and women in the REGARDS cohort to determine whether statin use modifies effects of alcohol consumption on the risk of all-cause mortality. Alcohol consumption, statin use, and data on potential confounders were assessed at baseline while occurrence of clinical events including death was assessed by telephone every 6 months. Participants were classified as never, past, moderate (≤2 drinks/day for men, ≤ 1 drink/day for women) and heavy drinkers (>2 drinks/day for men, >1 drink/day for women). Statin use was defined as use of any statin regardless of type or dose. Cox-regression analyses were used to test whether alcohol intake was associated with mortality and whether there was an interaction with statin use. Models included baseline age, sex, BMI, race, region, smoking, income, education, marital status, diabetes, stroke, hypertension, coronary artery disease, regular use of anti-inflammatory medications, alcohol use, statin use and alcohol*statin use interaction term.   Results:  Over a median follow-up of 6.1 years there were 3,076 deaths. Most participants (65%) consumed alcohol, but even among heavy drinkers (n=1,105), only 341 participants reported consuming >3 drinks/day. Statins were used by 31%, 36%, 32% and 28% of never, past, moderate and heavy drinkers, respectively. We observed a significant interaction between alcohol consumption and statin use with regard to risk of all-cause mortality ( P   1.12 (0.99-1.25), 0.73 (0.65-0.82) and 0.91 (0.73-1.13),  respectively, among non-statin users, while they were  0.88 (0.76-1.03), 0.87 (0.75-1.01) and 0.49 (0.32-0.75)  among statin users. In cross-sectional analyses of baseline data, alcohol intake was positively associated with HDL-C and inversely associated with CRP and triglycerides, with significant interactions between alcohol consumption and statin use for all three markers ( P  for interaction    Conclusions:  Statin use is common among heavy drinkers. Our data show that alcohol consumption at levels observed in this study is inversely associated with risk of all-cause mortality, and its effects may be synergistic to those of statins. Future studies with adequate sample size of heavy drinkers are needed to confirm these findings.
532. Cervical Spinal Cord Delivery of a Lentiviral Vector in SOD-1 Transgenic Mice
Authors: Diana Tanase, Qingshan Teng, Ajit A. Krishnaney, James K. Liu, Mary E. Garrity-Moses, Nicholas Mazarakis, Lucy E. Walmsley, Mimoun Azzouz, Nicholas M. Boulis
Journal: Molecular Therapy (2004)

Objective: Recent work has suggested that injection of lentiviral vectors might constitute means of therapeutic gene delivery to diseased motor neurons in ALS. However, as implied by the name, Amyotrophic Lateral Sclerosis, this disorder results in sclerosis of the spinal cord. In addition, axonal transport is altered in these animals. The present study attempts to characterize the behavioral impact as well as the distribution of gene expression in the CNS following direct spinal cord injection of the rabies G protein pseudotyped lentiviral vector, EIAV.LacZ, in control and SOD-1 transgenic mice.
292. Modification of the p53 Transgene of a Replication-Competent Adenovirus Improves p53 Stability and Cancer Cell Killing
Authors: WM Gommans, Marianne Rots, Pmj McLaughlin, SJ van Eert, Marco Harmsen, M Yamamoto, DT Curiel, Hidde Haisma
Journal: Molecular Therapy (2004)

Adenoviruses are widely used as vectors to deliver genetic material into cells. Although these vectors are currently the most efficient vectors used, they are not specific and not efficient enough to result in a good clinical outcome in the treatment against cancer. To increase the specificity, a transgene can be placed under the control of a tumor specific promoter, such as the epithelial glycoprotein-2 (EGP2) promoter. This promoter is active in a broad range of epithelial derived cancers. The length of the EGP2 promoter fragment used in initial studies is 3.4 kb. This promoter fragment showed in adenoviral context high activity and selectivity when tested both in vitro and in vivo. However due to limited space in the adenoviral genome, this promoter fragment is too large for the incorporation of several expression cassettes.
Activated macrophages promote hepatitis C virus entry in a tumor necrosis factor-dependent manner
Authors: Nicola F. Fletcher, Rupesh Sutaria, Juandy Jo, Amy Barnes, Miroslava Blahova, Luke W. Meredith, Francois-Loic Cosset, Stuart M. Curbishley, David H. Adams, Antonio Bertoletti, Jane A. McKeating
Journal: Hepatology (2013)

Macrophages are critical components of the innate immune response in the liver. Chronic hepatitis C is associated with immune infiltration and the infected liver shows a significant increase in total macrophage numbers; however, their role in the viral life cycle is poorly understood. Activation of blood-derived and intrahepatic macrophages with a panel of Toll-like receptor agonists induce soluble mediators that promote hepatitis C virus (HCV) entry into polarized hepatoma cells. We identified tumor necrosis factor α (TNF-α) as the major cytokine involved in this process. Importantly, this effect was not limited to HCV; TNF-α increased the permissivity of hepatoma cells to infection by Lassa, measles and vesicular stomatitis pseudoviruses. TNF-α induced a relocalization of tight junction protein occludin and increased the lateral diffusion speed of HCV receptor tetraspanin CD81 in polarized HepG2 cells, providing a mechanism for their increased permissivity to support HCV entry. High concentrations of HCV particles could stimulate macrophages to express TNF-α, providing a direct mechanism for the virus to promote infection. Conclusion: This study shows a new role for TNF-α to increase virus entry and highlights the potential for HCV to exploit existing innate immune responses in the liver to promote de novo infection events. (Hepatology 2014;59:1320-1330)