tbuckley/cabot-search huggingface dataset:
Abstract 2518: Development of a non-hydrolysable phosphotyrosine mimetic peptide based on a high affinity SHP2 substrate
Authors: Harshani R. Lawrence, Yiyu Ge, Andreas Becker, Yuan Ren, Yunting Luo, Jie Wu, Nicholas J. Lawrence
Journal: Cancer Research (2014)

Abstract The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a transducer of growth factor, cytokine, integrin, and hormone signaling pathways that regulate processes such as cell proliferation, differentiation, adhesion, migration, and apoptosis and plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with several types of leukemias, and solid tumors. This makes SHP2 an attractive target for developing new anticancer therapy. Several small molecules have been developed for inhibition of this important phosphatase, which serve as chemical tools to probe the role of SHP2 in disease and lead compounds for optimization. Nevertheless improvements are required to improve these lead compounds with better potency, selectivity and cell permeability. To gain structural insights for development of potent and selective Shp2 inhibitors, we synthesized a non-hydrolysable phosphotyrosine peptide mimetic, based on reported Shp2 substrate peptide sequences. The non-hydrolyzable phosphopeptide, containing the phosphotyrosyl surrogate difluoromethylphosphonate, was prepared by solid phase peptide synthesis methods from the known building block N-FMOCF2Pmp. We will present the synthesis of the peptide, analysis of Shp2 phosphatase inhibition, and binding of the phosphopeptide mimic to SHP2 by micro isothermal calorimetry. We will present a model for the binding mode of the peptide and its implications for the design of selective Shp2 inhibitors. Citation Format: Harshani R. Lawrence, Yiyu Ge, Andreas Becker, Yuan Ren, Yunting Luo, Jie Wu and Nicholas J. Lawrence. Development of a non-hydrolysable phosphotyrosine mimetic peptide based on a high affinity SHP2 substrate. [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 2518. doi:10.1158/1538-7445.AM2014-2518
An incident which changed my medical life: Something to celebrate
Authors: S. Pathak
Journal: BMJ (1999)

It happened over three decades ago—1963 to be precise, the year that I became a doctor. That year the Medical Council of India decreed that six months of internship were to be completed before the one year as a house officer, a total of 18 months of preregistration jobs. My first was on a surgical unit.

A friend and I decided to celebrate passing our qualification by cooking a special meal in the doctors' canteen, and by contributing equally to a quarter bottle of rum, priced six rupees, which was all we could afford. My ward duties were from 7 00 am to midday and 5 30 to 7 00 pm. I arrived at the ward for …
11. Reporter Gene-Based Analysis of rAAV Genome Circularization and Recombination
Authors: Douglas M. McCarty, Vivian Choi, Richard J. Samulski
Journal: Molecular Therapy (2004)

Adeno-associated virus (AAV) vector DNA persists in non-dividing cells largely as circular and concatameric episomes. We have created a set of self-complementary AAV (scAAV) split-gene vectors with which to dissect the DNA recombination events that lead to stable episome formation. The scAAV vector provides two important advantages for these assays: 1) it forms double-strand DNA immediately upon uncoating, thus mimicking the structure of the conventional rAAV after second-strand synthesis has taken place; 2) it allows control of the specific orientation of the coding sequences relative to the open (O) and closed hairpin (C) terminal repeat ends of the genome. One such vector was constructed to report with GFP expression when the genome had circularized (intramolecular recombination between O and C terminal repeats). Additional sets of scAAV vectors were constructed to report when specific intermolecular recombination events had taken place. These included O to C end joining, as well as O-O, and C-C. The efficiency of each such event was measured in the presence and absence of drugs which inhibited specific cellular factors or processes. We found that circularization of rAAV genomes is extremely efficient in HeLa and HEK293 cells, with >97% of infecting genomes in the circular configuration before 24 hr. post-infection. Importantly however, circularization was not a prerequisite for gene expression. We have extended these studies to real-time reporting of rAAV genome circularization in mouse muscle tissue. For intermolecular events, we found that C-C recombination is the most efficient, followed by O-C and O-O events. Under conditions of DNA synthesis inhibition, recombination involving closed ends was most sensitive, with the result that the incidence of each type of event was reduced to approximately the same value. Inhibition of topoisomerase II with Etoposide resulted in strong, but non-specific, inhibition of each type of recombination. In contrast, inhibition of topoisomerase I with campothectin specifically reduced events involving the closed hairpin end, to the extent that the order of recombination preference was inverted relative to the untreated cells, with O-O most efficient, followed by O-C and C-C. Our results strongly suggest the involvement of a DNA synthesis step in rAAV genome circularization and concatemerization, as well as a requirement for topoisomerase I in processing the closed hairpin ends.
Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α
Authors: Ivan D Mascanfroni, Maisa C Takenaka, Ada Yeste, Bonny Patel, Yan Wu, Jessica E Kenison, Shafiuddin Siddiqui, Alexandre S Basso, Leo E Otterbein, Drew M Pardoll, Fan Pan, Avner Priel, Clary B Clish, Simon C Robson, Francisco J Quintana
Journal: Nature Medicine (2015)
Exhaled breath condensate pH in assessment of childhood asthma control
Authors: Igor Klimanov, Svetlana Soodaeva, Tatyana Eliseeva, Natalia Popova, Lidiya Nikitina, Nailya Kubysheva, Natalia Geppe
Journal: European Respiratory Journal (2014)

Exhaled breath condensate (EBC) pH value is considered as a marker of airway inflammation in asthma, but the possibility of its usage for asthma monitoring in children is not completely obvious.  The study included 55 children with atopic asthma aged 5 - 17 years with diagnosed upper respiratory tract infection. Asthma control was evaluated by the ACQ test, which was carried out in two variants: ACQ-5 (symptoms during the week) and ACQ-diary (symptoms during the day). EBC was collected using the “R-tube”. The pH values were measured by the pH-meter after 10 minutes degassing with argon at flow rate of 250 ml/min.  There were no differences in EBC pH between the groups with different asthma control according to ACQ-5 test: full control (ACQ-5 1,5) – (6,85±0,63); p=0.84. While using ACQ-diary test, it was found that the average EBC pH decreased monotonously with increase of symptoms severity: ACQ-diary 1,5 – (5,94±0,40); p=0.0001. The EBC pH is more likely to characterize the momentary state of a patient and fails to be a marker of the long-lasting state of the respiratory tract.  Thus, the deaerated EBC pH may be useful tool for monitoring of asthma control in asthmatic children. However, this parameter is informative only for the evaluation of the current state of the airways due to its high lability.
Strategies for assessing the degree of photodamage to skin: a systematic review of the literature
Authors: L. Baillie, D. Askew, N. Douglas, H.P. Soyer
Journal: British Journal of Dermatology (2011)

As our understanding of the role of ultraviolet (UV) radiation exposure in causing skin cancer continues to be enhanced, it is important that clinicians and researchers are familiar with the various methods for assessing photodamage to skin. This paper provides a systematic review of the published literature on invasive and noninvasive methods used to quantify lifetime UV exposure ('photoageing'). Clinical examination, histopathology, immunohistochemistry, skin surface topography and ultrasound, in addition to newer technologies such as reflectance confocal microscopy, optical coherence tomography and multiphoton tomography, are reviewed. It is concluded that histopathological solar elastosis alone should not be viewed as a 'gold standard' diagnostic test and that there is no single method available to give accurate quantification of the degenerative changes associated with photodamage. Although additional research into sensitivity and specificity is still needed, skin surface topography currently has the most support in the literature as a valid and reliable noninvasive tool for the assessment of photoageing.
Abstract 13921: Head-to-head Comparison of Real-Time Myocardial Perfusion Echocardiography vs Cardiac Magnetic Resonance in Patients with Revascularized ST-Elevation Myocardial Infarction: Prognostic Implications
Authors: Sahar S Abdelmoneim, Nandan S Anavekar, Thomas A Foley, Matthew Martinez, Lara F Nhola, Runqing Huang, Jae K Oh, Sharon L Mulvagh
Journal: Circulation (2014)

Objectives: To compare real-time myocardial perfusion echocardiography (RTMPE) with myocardial-delayed enhancement imaging on cardiac magnetic resonance (CMR) for prediction of cardiac events (CE) in revascularized STEMI patients (pts).

Methods: Consecutive acute STEMI pts with acute reperfusion by PCI and/or thrombolysis were studied. RTMPE (Definity) and CMR were performed within 1.04± .8 days & 1.7±1.2 days from PCI, respectively. Visual assessments of perfusion by RTMPE and transmural necrosis extent by CMR in 17-segments were graded independently as:0=normal/no scar;1=hypoperfused/non transmural scar;2=absent perfusion/transmural scar. Perfusion score indices PSI RTMPE & PSI CMR were calculated [sum of segmental perfusion scores / segments]. CMR infarct mass (g) and RTMPE myocardial blood flow [MBF dB/sec] were quantified. Pts were followed for CE [death, nonfatal MI, revascularization, angina, and heart failure]. Cox regression analysis was done.

Results: All 27 pts [age 62 ±14; follow-up 3.5±2.6 yrs] had TIMI grade 3 flow of revascularized infarct vessel. CE occurred in 17 (63%) (death=5,STEMI=1, angina=4,CABG=1,PCI=2,HF=4). CE pts had higher PSIRTMPE , PSICMR , infarct mass, and lower MBF Figures A,B . PSIRTMPE cutoff .3 had AUC .856 [82% sensitivity,70% specificity], while PSICMR cutoff .2 had AUC .765 [76 % sensitivity, 60% specificity]. Pts with PSICMR ≥ .2; infarct mass ≥ 14; PSIRTMPE≥ .3 and MBF ≤.557 had increased CE [log-rank X2 1.6, P=.21; 5.7, P=.02; 4.3, P=.04,and 5.1, P=.02 respectively]. Infarct mass and MBF were independent predictors of CE after adjusting for risk factors [hazard ratios: 20.9 (95% CI 1.8-256) P=.02 and 8.1 (95% CI 1.5-78) P =.01, respectively].No pts had side-effects reported.

Conclusions: RTMPE performed comparably to CMR in excellent prediction of subsequent cardiac events in revascularized STEMI pts. These findings support a prognostic role for this novel, readily available, noninvasive, bedside imaging method.

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Discovery of small molecule IAP antagonists: A structure-based drug design approach to targeting protein-protein interactions
Authors: Julian Chen
Journal: Cancer Research (2008)

SY38-03   Apoptosis is a critical process regulating cell growth. Defects in apoptosis favor cellular hyperproliferation and are common in cancer. Through direct binding and inhibition to caspases, inhibitors of apoptosis proteins (IAPs) represent one set of anti-apoptotic modulators exploited by cancer cells to down-regulate apoptosis; IAPs are therefore potential anti-cancer targets and small molecule IAP antagonists provides a molecular approach to potential therapeutical intervention. At Novartis we have discovered potent, novel small molecule IAP antagonists that posses desirable drug-like properties and showed in vivo anticancer efficacy in human cancer bearing mouse models. This presentation will discuss our progress toward the small molecule lead discovery using peptido-mimetics of SMAC, a natural peptide antagonist of IAPs. Focus will be given on the structure-based lead optimization for potency and of drug-like properties of these IAP antagonists. Finally, in vitro and in vivo data will be presented to provide proof of concept for IAPs as novel anticancer targets and to demonstrate the therpeutical potential of our novel IAP antagonists.
The Transformation of US Physicians
Authors: Victor R. Fuchs, Mark R. Cullen
Journal: JAMA (2015)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Imported fresh sugar peas as suspected source of an outbreak of Shigella sonnei in Denmark, April – May 2009
Authors: L Muller, T Jensen, R F Petersen, K Mølbak, S Ethelberg
Journal: Eurosurveillance (2009)

We report on an outbreak of Shigella sonnei infections involving ten cases notified through the laboratory surveillance system in Denmark in April and May. The likely source was consumption of fresh, raw sugar peas (sugar snaps) imported from Africa. This conclusion was based on interviews with cases and on the occurrence of a similar outbreak one month later in Norway. Fresh imported produce may occasionally be contaminated with pathogenic bacteria even when sold as ready-to-eat.
Effects of chronic cocaine abuse on postsynaptic dopamine receptors
Authors: N D Volkow, J S Fowler, A P Wolf, D Schlyer, C Y Shiue, R Alpert, S L Dewey, J Logan, B Bendriem, D Christman
Journal: American Journal of Psychiatry (1990)

To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [18F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [18F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.
Oral Antiplatelet Therapy
Authors: Javier Borja
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
Cleaning Up the Women's Health Center
Authors: Gary Stein
Journal: JAMA (2003)

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
Imiquimod simultaneously induces autophagy and apoptosis in human basal cell carcinoma cells
Authors: S-W. Huang, K-T. Liu, C-C. Chang, Y-J. Chen, C-Y. Wu, J-J. Tsai, W-C. Lu, Y-T. Wang, C-M. Liu, J-J. Shieh
Journal: British Journal of Dermatology (2010)

Background Imiquimod shows antitumour activity through the stimulation of cell-mediated immunity in vivo. Recent studies have shown that imiquimod promotes apoptosis in melanoma cells and induces autophagy in macrophage cell lines. Objectives To evaluate the imiquimod-induced apoptosis, autophagy and their relationship in a basal cell carcinoma (BCC) cell line. Methods Cell viability was determined by XTT test. Apoptosis was evaluated by DNA content assay, annexin V/propidium iodide staining assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling assay. Autophagy was determined by LC3 immunoblotting, EGFP-LC3 puncta formation and quantification of acidic vesicular organelles with acridine orange staining. The temporal and spatial differences of imiquimod-induced apoptosis and autophagy were examined by immunoblotting and simultaneously monitored by staining the EGFP-LC3 transfected cells with caspase 3 fluorogenic substrate. We inhibited the apoptosis and autophagy by pancaspase inhibitor and siRNA for Beclin 1 or Atg5, respectively, to evaluate the interplay between imiquimod-induced apoptosis and autophagy. Results We found that imiquimod induces autophagy and apoptosis in BCC cells in a time- and dose-dependent manner. Imiquimod not only induced EGFP-LC3 puncta formation for autophagy, but also simultaneously activated an apoptotic caspase cascade in the same cells. Both apoptosis and autophagy induced by imiquimod cooperate to cause BCC cell death. However, inhibition of imiquimod-induced apoptosis increased the strength of autophagy, and inhibition of imiquimod-induced autophagy further promoted cell apoptosis. Conclusions This study not only demonstrates that imiquimod can directly induce autophagy and apoptosis in BCC cells, but also shows the cooperation and coordination between these two processes to induce cell death.
Abstract 18414: Malat1 Regulates the Inflammatory Response of Endothelial Cells
Authors: Katharina Michalik, David John, Wei Chen, Shizuka Uchida, Andreas Schober, Christian Weber, Reinier A Boon, Stefanie Dimmeler
Journal: Circulation (2014)

Laminar blood flow has an anti-inflammatory effect on endothelial cells (ECs) and prevents local atherosclerotic lesion formation. Long non-coding RNAs (lncRNAs) have been described to play a role in many biological processes, including epigenetic regulation of gene expression. We previously showed that the lncRNA MALAT1 is highly expressed in ECs and plays a role in angiogenesis. Since we showed that MALAT1 is induced by anti-inflammatory laminar shear stress (3.4+0.6 fold), we assessed whether MALAT1 regulates the inflammatory response of ECs. Therefore, we used several siRNAs and LNA GapmeRs to specifically silence MALAT1. We noticed that targeting different regions of MALAT1 showed opposite effects on TNFα-induced inflammatory response. Whereas 3 different siRNAs and GapmeRs directed against the 5’end enhanced the TNFα-induced expression of E-selectin, VCAM1 and ICAM1, a GapmeR directed against the 3’end reduced the inflammatory response of ECs (Fig.1). To determine whether these effects are due to targeting of different transcript variants, we designed different PCR primers and identified a novel 1.3 kb 5’ variant of MALAT1, which was confirmed by deep sequencing. Interestingly, the two transcript variants are inversely regulated in human atherosclerotic plaques. Whereas the anti-inflammatory 1.3 kb 5’ variant was down-regulated in advanced plaques in AHA classification type 3 vs. 4 (42%+9%), the long pro-inflammatory variant was increased (158+28%). We further characterized MALAT1 variants and showed that both are transcribed by RNA Polymerase II and are nuclear localized. RNA-IP experiments showed that the short MALAT1 variant binds to Histone H3 whereas the long MALAT1 predominantly binds to H3K27me3 suggesting that the variants exhibit different epigenetic effects. In summary, our data identify for the first time a new 5′ variant of MALAT1, which reduced EC activation by TNFα, whereas the long MALAT1 augments the inflammatory activation of ECs.
Doctors need to “sell themselves” to get legislative change
Authors: Robert Ivker
Journal: BMJ (2001)

Doctors need to “sell themselves” more effectively to the public if they are to achieve legislative results, Senator Gordon Smith from Oregon told an audience of cancer specialists earlier this month.

Speaking at the annual meeting of the American College of Radiation Oncology in California, the senator said that the American public did not fully appreciate the contribution that doctors make to society.

As a Republican member of several committees that will influence healthcare legislation, Senator Smith laid out several specific steps he has taken to address the problem of uninsured Americans. The …