tbuckley/cabot-search huggingface dataset:
Abstract 2581: Indolequinone mechanism-based inhibitors of quinone reductases: Structural basis for selective inhibition of NQO2 relative to NQO1
Authors: Chao Yan, Marine Dufour, David Siegel, Philip Reigan, Joe Gomez, Biehuoy Shieh, Christopher J. Moody, David Ross
Journal: Cancer Research (2011)

Abstract There are two quinone reductases that occur in mammalian systems NAD(P)H:quinone oxidoreductase 1 (NQO1, EC 1.6.99.2) and NRH:quinone oxidoreductase 2 (NQO2, EC 1.10.99.2). NQO1 has been shown to be up-regulated in many types of human solid cancer; whereas NQO2 has been shown to be highly expressed in leukemias. In order to explore their potential as therapeutic targets, we have developed potent and selective mechanism-based inhibitors for both enzymes centered on the indolequinone pharmacophore. Previously, we characterized ES936 (5-methoxy-1,2-dimethyl-3-(4-nitrophenoxy)methylindole-4,7-dione) as an efficient mechanism-based inhibitor of NQO1 and we have now developed a series of indolequinones as mechanism-based inhibitors of NQO2. Substitution of the 5-methoxy group in ES936 with an aminoalkylamino side chain generated potent mechanism-based inhibitors of NQO2 that did not efficiently inhibit NQO1. NQO2 inhibition was observed with compounds with 5’-aminoalkyl chains that varied from 3 to 8 carbons in length, with maximal inhibition observed with compounds that possessed 5’-chain lengths of between 3 to 5 carbons. Compounds with substitutions at the 6-position were not efficient mechanism-based inhibitors of NQO2. As previously observed for a series of NQO1 mechanism-based inhibitors, structural requirements for efficient inhibition of NQO2 also included a substituent at the 3-position capable of leaving to generate a reactive iminium electrophile following enzymatic reduction. Selected indolequinones were tested for NQO2 inhibition using the human leukemia cell line K562 and were found to inhibit NQO2 activity in K562 cells at nanomolar concentrations while not affecting NQO1 activity. Computational-based molecular modeling simulations demonstrated the substantial difference between the active site of NQO1 and NQO2 and ESI-LC/MS provided possible explanations for selective enzyme inhibition. These indolequinones represent the first mechanism based inhibitors of NQO2 to be characterized. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2581. doi:10.1158/1538-7445.AM2011-2581
Abstract P1-04-10: PDGFRA signaling in Inflammatory breast cancer.
Authors: M Joglekar, K van Golen
Journal: Cancer Research (2012)

Abstract Inflammatory breast cancer is the most lethal form of locally advanced breast cancer. It is clear from the recent research advancements in IBC that it is entirely a different entity, not only in its clinical presentation but also in its molecular expression profile. Therefore, it is essential to carry out molecular expression studies in IBC compared to non-IBC as well as to pursue these differences to study their effects on IBC phenotype. In collaboration with the Translational Cancer Research group in Antwerp Belgium, our lab has recently found that PDGFRA is significantly over expressed in IBC patient samples (between 15–36%) compared to non-IBC patient samples. This project focuses on identifying the PDGFRA activation signature in SUM149 IBC cells. Upon ligand stimulation, PDGFR can either homo or heterodimerize (AA, AB, BB) and produce an array of signaling events responsible for cell growth, cell proliferation, cell differentiation in normal cells as well as in several cancer cells. SUM149 and SUM190 cells lack ER, PR and HER-2 expression and hence are named triple negative IBC cells. Triple negative breast cancers are highly aggressive in nature and therefore suffer from poor prognosis. We seek to determine if signaling via over expressed PDGFRA could be a potential surviving factor in producing such fast growing and highly invasive IBC tumors. Preliminary data on immunostaining of PDGFRA with and without permeabilization suggests intracellular localization of PDGFRA. We also know that SUM149s and SUM190s express all four PDGF ligands (A, B, C, D). This unusual expression of all the PDGF lignads suggests the self-sufficiency of these cells for PDGFRA signaling. In other words, these cells maintain constitutively active PDGFRA via intracrine/autocrine loop. Protein expression of active PDGFRA was studied by using two different phospho specific PDGFRA antibodies (Tyr 1018 and Tyr 849) without any prior stimulation by PDGF ligands. Moreover our data shows that PDGFR- activation in IBC, unlike in n-IBC, is PDGF-C driven. Possibility of such intracrine/autocrine loop could significantly increase the overall PDGFRA signaling in IBC cells and hence can produce fast growing aggressive IBC tumors. Thus targeting PDGFRA, an important biomarker in IBC could stand as a novel and systematic therapeutic approach. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-10.
P230 Facilitating End-Of-Life Discussions in Users of Home Mechanical Ventilation That Have a Life-Limiting Neuromuscular Disease
Authors: J Palmer, N Stephen, R Endacott
Journal: Thorax (2012)

<h3>Introduction and Objectives</h3> There are many individuals living in the United Kingdom with a neuromuscular disease which will cause their death. Many use home mechanical ventilation (HMV). Discussing end-of-life care with patients with life-limiting disease is currently high on the health agenda. Whilst the published guidance does not provide evidence that patients wish to be involved in these discussions, the knowledge base tends to support it. There are few studies which specifically investigate whether those with progressive neuromuscular disease want to be involved or what facilitates such conversations. We examined the experience of HMV patients with neuromuscular disease with regards end of life discussions. <h3>Methods</h3> A generic qualitative research approach was employed. Purposive sampling was utilised. Individuals, volunteered to participate in a face-to-face interview. The interview transcripts were analysed using a thematic content approach to identify common themes. <h3>Results</h3> Interviews were conducted with 9 individuals; 5 male, 4 female with a mean age of 58 years (range 31–74). Five participants had Motor Neuron Disease (MND). Four had less progressive disease. Two participants used continuous tracheostomy ventilation; the others used HMV predominantly at night. Five denied that they had taken part in a professional led end-of-life conversation. Four participants have since died. The key findings indicate that for constructive dialogue to take place most individuals required a prompt or cue from a care professional. Not all had one. Once received most patients would engage in conversations as long as the timing, conditions and professional were appropriate. The need to remain positive and to receive adequate information were strong themes throughout the interviews. The presence of relatives or significant others was a barrier to productive conversations in those with more stable disease but a facilitator to those with MND. <h3>Conclusion</h3> Despite the need for individuals to remain positive, useful discussions can take place if patients are approached to do so by a knowledgeable professional with the correct skills at an appropriate place in the disease trajectory. If such discussions do take place then patients can find these rewarding and they can have a positive effect on their lives.
Effect of Ketosis on Respiratory Sensitivity to Carbon Dioxide in Obesity
Authors: Peter I. Fried, Patricia A. McClean, Eliot A. Phillipson, Noe Zamel, Frederick T. Murray, Errol B. Marliss
Journal: New England Journal of Medicine (1976)

We investigated whether the respiratory defect in the obesity-hypoventilation syndrome might respond to dietary manipulation. The effects of hypocaloric ketogenic regimens on the ventilatory response to carbon dioxide were studied in a manner excluding changes in weight or thoracic mechanics as factors. Six obese subjects with hyporesponse (less than 1.1 1/min/mm Hg) and 12 with normal response were fasted or given a diet containing 400 kcal per day of protein. During ketosis carbon dioxide response more than doubled in those with hyporesponse (0.8 +/- 0.1 to 1.8 +/- 1/min/mm Hg, P less than 0.05) but was unchanged in those with normal response. This improvement could not be accounted for by changes in weight, pulmonary function, pH or degree of ketosis between the two groups. However, a significant positive (r = 0.70; P less than 0.001) correlation between ketone-body concentrations and carbon dioxide response was observed in subjects with hyporesponse. These results indicate that depressed sensitivity to carbon dioxide in obese patients can be increased by dietary manipulation.
Pseudomyxoma Peritonei Associated with Cholesterosis
Authors: C. G. Tedeschi, E. A. Gaston, Ethan A. Brown
Journal: New England Journal of Medicine (1949)

WERTH,1 in 1884, first called attention to the unusual finding of a gelatinous exudate, partly free and partly encysted, in the peritoneal cavity of a woman bearing a "pseudomucinous cyst" of the ovary. He named the process "pseudomyxoma peritonei" and traced its origin to the rupture of the ovarian cyst and subsequent implant of the cystic contents on the peritoneal membranes. In 1901 Fraenkel2 found a similar condition in a man with a ruptured mucocele of the appendix. Because of the gross similarity of patterns he considered it appropriate to retain the denomination previously proposed by Werth.1 Since then quite . . .
Organized Urachal Abscess Mimicking Urachal Carcinoma on FDG PET/CT
Authors: Aisheng Dong, Changjing Zuo, Yang Wang, Jianping Lu, Haiyun Zhu
Journal: Clinical Nuclear Medicine (2013)

Urachal inflammation is rarely seen in adults. Two patients with suspected abdominal tumor underwent FDG PET/CT. One patient showed an irregular hypermetabolic mass anterosuperior to the bladder. The other patient showed a thick-walled cystic mass with strong FDG uptake extending from the bladder dome to the anterior abdominal wall. Urachal carcinomas were suspected based on imaging findings. Both patients underwent complete resection of the masses. However, both masses were organized urachal abscesses confirmed by pathological examination. These two cases highlight that differentiation between organized urachal abscess and carcinoma is difficult on the basis of imaging.
434 ENHANCED INTERLEUKIN-2 DIPHTERIA TOXIN CONJUGATE-INDUCED GROWTH SUPPRESSION IN RETINOIC ACID-TREATED HYPOXIC HEPATOCELLULAR CARCINOMA CELLS
Authors: S.J. Myung, J.H. Yoon, B.H. Kim, G.E. Jung, J.H. Lee, H.S. Lee, J.S. Lee, Y.J. Lee
Journal: Journal of Hepatology (2008)
PTU-228 Predicting difficult colonoscopy using the St Mark's difficult colonoscopy scoring system: a pilot study
Authors: M Nakamura, A Murino, E Despott, N Suzuki, L Bourikas, R Man, C Fraser
Journal: Gut (2012)

<h3>Introduction</h3> Colonoscopy can sometimes be difficult. This may be due to a number of factors such as age, gender, increased colon length, waist/hip ratio &lt;1, BMI&lt;22, abdominopelvic surgery and a history of constipation. Colonoscopists tend to develop their own strategies based on their personal experience and the availability of specialised equipment. A scoring system based on these factors could be a useful predictor of difficult colonoscopy with the advantage that such a score could be calculated prior to the procedure. We therefore developed an evidence based difficult colonoscopy score (DCS), incorporating factors associated with difficult colonoscopy. The aim of this study was to validate the reliability of the proposed St Mark9s DCS evaluating the relationship between each factor and caecal incubation time. <h3>Methods</h3> Patients referred for routine colonoscopy were recruited. 30 patients were prospectively selected. Each patient was screened using a questionnaire. Colonoscopies were started with an adult colonoscope, but if needed, alternative options such as a paediatric colonoscope or real time magnetic imager were made available on request. <h3>Results</h3> The overall caecal incubation rate was 97% (29/30). One patient was excluded due to a colonic stricture. The median DCS was 3 (range 0–6). Median insertion time was 8 min (range 3–23). In three patients colonoscopists changed to an alternative option during colonoscopy. There was a significant correlation between the DCS and insertion time (r=0.511, p=0.005, Pearson9s correlation coefficient). Moreover, if the DCS was five or more, caecal intubation time was &gt;15 min suggesting a strong correlation. The significant factors by univariate analysis influencing a caecal intubation time of more than 15 min were “Waist/hip ratio &lt;1 and/or BMI&lt;22”, “over 60 years old” and “Constipation”. Multivariate analysis suggested the most significant factor for difficult colonoscopy was a history of constipation. <h3>Conclusion</h3> This pilot study has shown the DCS could be a useful tool for the prediction of difficult colonoscopy. This could be of benefit when scheduling lists for training and choosing the level of experience of colonoscopists before procedures are performed. A large study is planned. <h3>Competing interests</h3> None declared.
Changes in Energy Expenditure Resulting from Altered Body Weight
Authors: Rudolph L. Leibel, Michael Rosenbaum, Jules Hirsch
Journal: New England Journal of Medicine (1995)

No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly.
NATIVE T1 MAPPING SUPPORTS PATHOGENESIS OF LEFT VENTRICULAR APICAL SPARING IN CARDIAC AMYLOIDOSIS
Authors: Kunal D. Patel, Brett Sperry, Dermot Phelan, Mazen Hanna, Amr Barakaat, Zoran Popovic, Deborah Kwon, Christine Jellis
Journal: Journal of the American College of Cardiology (2016)
Efficient Nonviral Cutaneous Transfection
Authors: Jill Glasspool-Malone, Stella Somiari, Joseph J. Drabick, Robert W. Malone
Journal: Molecular Therapy (2000)

<h2>Abstract</h2> Preclinical in vivo rodent, porcine, and primate experiments aimed at enhancing nonviral transgene delivery to skin have been performed. These investigations have identified a compound (aurintricarboxylic acid or ATA) that enhances transfection activity of "naked" plasmid and pulsed electrical fields (electroporation or EP) that synergistically boosts transgene expression to an average of 115-fold more than that observed with free DNA (P < 0.00009). When plasmid is intradermally injected with or without ATA, the transfected cells are typically restricted to the epidermis. However, when electroporation is added after the same injection, larger numbers of adipocytes and fibroblasts and numerous dendritic-like cells within the dermis and subdermal tissues are transfected. This advance creates new opportunities for cutaneous gene therapy and nucleic acid vaccine development.
Systematic identification of genetic influences on methylation across the human life course
Authors: Tom R. Gaunt, Hashem A. Shihab, Gibran Hemani, Josine L. Min, Geoff Woodward, Oliver Lyttleton, Jie Zheng, Aparna Duggirala, Wendy L. McArdle, Karen Ho, Susan M. Ring, David M. Evans, George Davey Smith, Caroline L. Relton
Journal: Genome biology (2016)

The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age. We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution. DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.
The Importance of Tc-MAA SPECT/CT for Therapy Planning of Radioembolization in a Patient Treated With Bevacizumab
Authors: Hojjat Ahmadzadehfar, Amir Sabet, Carsten Meyer, Elham Habibi, Hans-Jürgen Biersack, Samer Ezziddin
Journal: Clinical Nuclear Medicine (2012)

A 76-year-old man with colorectal cancer and hepatic metastases was referred to us for radioembolization of the liver. Angiography with 99mTc-MAA SPECT/CT was performed 8 weeks after the discontinuation of bevacizumab. 99mTc-MAA SPECT/CT showed a diffused intrahepatic tracer distribution with no focally accentuated accumulation in the tumorous region. The test was repeated 6 weeks later and Tc-MAA SPECT/CT showed this time a tumor accentuated tracer accumulation in the liver. Subsequently, the patient was treated with resin microspheres. Tc-MAA SPECT/CT allows a better evaluation of intrahepatic tracer accumulation of Tc-MAA and facilitates the determination of the most appropriate treatment time.
Ring-like FDG Uptake in Acute Cholecystitis
Authors: CHIA-HUNG KAO
Journal: Clinical Nuclear Medicine (2003)

From the Department of Nuclear Medicine and PET Center, China Medical College Hospital, Taichung, Taiwan Received for publication July 10, 2002. Accepted August 16, 2002. Reprint requests: Chia-Hung Kao, Department of Nuclear Medicine and PET Center, China Medical College Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail: [email protected]
Gastrointestinal Bleeding, Munchausen Style
Authors: MYROSIA M. FOGA, WILLIAM D. LESLIE
Journal: Clinical Nuclear Medicine (2003)

From the Department of Nuclear Medicine, St. Boniface General Hospital, Winnipeg, Canada Received for publication October 4, 2001. Revision accepted September 17, 2002. Correspondence: William D. Leslie, Department of Medicine (C-5121), St. Boniface General Hospital, 409 Tache Avenue, Winnipeg, Canada R2H 2A6. E-mail: [email protected]
Enrique Gonzalez Martínez
Authors: Francisco-Javier Campos
Journal: New England Journal of Medicine (1967)

ONE of the greatest poets of the Americas was the Mexican physician, Enrique González Martínez, who was born in 1871 in Guadalajara, in the State of Jalisco, the son of a hard-working schoolteacher and an intelligent and dynamic mother.González Martínez was the only child for thirteen years, when a sister was born, and he grew up to be a lonely and sensitive youth, acquiring from his parents an early interest in the beauties of poetry and literature.After elementary school he entered the Lyceum, where he gained a wide knowledge of the humanities. As a medical student at the . . .
ANÁLISIS DEL PAPEL DE LAS ANOMALÍAS DE FUSIÓN DUCTAL PANCREÁTICA COMO FACTOR DE RIESGO DE DESARROLLO DE PANCREATITIS POST-CPRE
Authors: JJ Vila Costa, C Prieto, M Gómez, M Garaigorta De Dios, E Rubio, M Basterra, F Bolado, J Urman, I Fernádez Urién, FJ Jiménez
Journal: Endoscopy (2013)

Introducción: Se ha postulado la asociación entre morfología ductal pancreática y pancreatitis post-CPRE (PpostCPRE). Objetivo: Evaluar la asociación entre anomalías de fusión pancreática (AFP) y PpostCPRE. Material y Método: Revisamos las wirsungrafías de las CPRE pancreáticas realizadas en nuestro centro (junio/09-junio/13) clasificando la fusión ductal: Fusión Normal (FN), fusión del conducto dorsal y Santorini con rama superior del conducto ventral; Ansa Pancreática (AP), fusión conducto dorsal con rama superior del conducto ventral pero Santorini con rama inferior; Bucle Pancreático (BP), fusión del conducto dorsal con rama inferior del conducto ventral; y Pancreas Divisum (PD), no fusión. Las wirsungrafías incompletas no se analizaron. En conjunto, la AP, BP y PD fueron considerados AFP. Comparamos la incidencia de PpostCPRE en AFP vs. FN. Resultados: Realizamos 134 CPRE pancreáticas en 68 pacientes, pudiendo determinar el tipo de fusión ductal en 56 pacientes (40 varones). 27 tenían antecedentes de pancreatitis aguda, 28 de pancreatitis crónica. Las mujeres presentaron mayor porcentaje de AFP (69% vs. 37%, p = 0,04). 30 pacientes tenían FN y 26 AFP (10 AP, 3 BP, 13 PD). Hubo complicaciones post-CPRE en 8 pacientes (14%), en 5 de ellos pancreatitis (8,9%). De forma aislada únicamente el BP se asoció al desarrollo de PpostCPRE (67% vs. 11,3%, p = 0,019). La incidencia de PpostCPRE en AP y PD fue de 10% y 15,4% respectivamente. La incidencia de PpostCPRE fue superior en las AFP frente a FN (19,2% vs. 0%, p = 0,017) manteniéndose esta significación al ajustar por sexo (p = 0,017). El antecedente de pancreatitis aguda o crónica, sexo y colocación de prótesis pancreática no influyeron en la PpostCPRE (p > 0,05). Conclusiones: Las AFP constituyen un factor de riesgo de PpostCPRE por lo que determinar morfológicamente la fusión ductal podría ser útil de cara a prevenir dicha complicación.
Electrophoretic Analysis of Serum Proteins in Infants and Children
Authors: J. William Oberman, Krikor O. Gregory, Frederic G. Burke, Sydney Ross, E. Clarence Rice
Journal: New England Journal of Medicine (1956)

THE rapid accumulation of pediatric literature describing the occurrence in certain children of the recently recognized clinical entity, congenital agammaglobulinemia (hypogammaglobulinemia),1 2 3 has stimulated further research into the changes in the serum-protein fractions produced by other illnesses in patients in the pediatric age group. Before investigation of the alteration of serum-protein patterns in pathologic states in children can be performed, however, it is necessary to establish the normal range of values of the separate protein fractions in young infants and children. The data4 5 6 7 8 9 10 on this subject are sparse, and were compiled mainly in the era before filter-paper electrophoresis; in addition most . . .
Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1
Authors: Paul G. Richardson, Todd M. Zimmerman, Craig C. Hofmeister, Moshe Talpaz, Asher A. Chanan-Khan, Jonathan L. Kaufman, Jacob P. Laubach, Dharminder Chauhan, Andrzej J. Jakubowiak, Steven Reich, Mohit Trikha, Kenneth C. Anderson
Journal: Blood (2016)