tbuckley/cabot-search huggingface dataset:
Abstract 223: Oncogenic resistance of Akt kinases to dephosphorylation through an ATP-dependent molecular switch
Authors: Tung Chan
Journal: Cancer Research (2012)

Abstract The serine/threonine Akt protein kinases (Akt1, Akt2 and Akt3) affect multiple cellular functions associated with “hallmark” properties of cancer, such as cell growth and survival, differentiation, metabolism and migration. Hyperphosphorylation of a threonine residue (Thr308 in Akt1) in the activation loop of Akt kinases is a prerequisite for the deregulated Akt activity frequently that is observed in neoplasia. Conversely, phosphatases including type 2A serine/threonine phosphatase (PP2A), reverse Akt phosphorlyation and activity. Here, we describe a new layer of control of Akt phosphorylation that points to ATP binding pocket occupancy as a means to decelerate Akt dephosphorylation. We show that targeting Akt kinases to the cell membrane markedly reduces the ability of phosphatases to dephosphorylate Thr308. This effect depends on the occupancy of the ATP binding pocket by either ATP or ATP competitive Akt kinase inhibitors (A443654 or G690693). To reconstitute this effect, we use purified phosphatases and Akt proteins to show that ATP markedly inhibits the dephosphorylation of phospho-Thr308 in vitro. Mutational analysis reveals that Arg273 in Akt1 and the corresponding Arg274 in Akt2 are essential for shielding Thr308 against dephosphorylation. While the binding of ATP and several ATP “mimic” inhibitors, ATP-γS, A-443654 and G690693 inhibits Akt dephosphorylation, the binding of other closely related molecules, ADP, ADPβS and isoquinoline sulphonamide (IQS, Ki 0.23uM) does not block dephosphorylation, suggesting unique determinants in the γ-phosphate of ATP that regulate Akt dephosphorylation. These results suggest that occupancy of the ATP-binding pocket of Akt kinases stabilizes a conformational state of the Akt kinase domain that restricts phosphatase access to phospho-Thr308, thereby sustaining Akt phosphorylation. Finally, we determine that phosphorylated Akt kinases in untransformed cells are subject to rapid dephosphorylation. However, in several cancer-derived cell lines, phosphorylated Akt kinases are highly resistant to dephosphorylation and the resistance depends on ATP-occupation. In addition, dephosphorylation resistance provides a mechanistic explanation for the ‘paradoxical’ phosphorylation of Akt previously described for ATP competitive inhibitors, A443654 and G690693. Also, dephosphorylation resistance may be the converging point of the oncogenic signals that induce Akt hyperactivation. Exploration of structures and amino acids involved in this process may hold the key to developing the next generation of pharmacological agents that could promote normal Akt physiology while inhibiting cancer cells for more positive results in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 223. doi:1538-7445.AM2012-223
OP0144 Validation of the rabbit risk score for serious infections:
Authors: A. Strangfeld, B. Manger, C. Eisterhues, A. Krause, J. Listing, A. Zink
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Recently we published a score [1] which enables the calculation of the risk of serious infections in individual patients with rheumatoid arthritis (RA) treated either with TNFα inhibitors or conventional DMARDs. Our original analysis was based on patients enrolled in the German biologics register RABBIT between May 2001 and December 2006. Taking changing risks over time (resulting from selection processes and clinical improvement) into account our data provided, for the first time, detailed information about the expected absolute risk of serious infection in individual patients. <h3>Objectives</h3> To evaluate these findings in an independent sample of patients not included in the previous analysis. <h3>Methods</h3> We used data from patients enrolled in RABBIT after 1st of January 2009 at start of treatment with TNFα inhibitors or conventional DMARDs. Using the RABBIT risk score, we calculated for each patient the expected likelihood of a serious infection based upon the individual risk profile. The expected numbers of serious infections were then compared to the observed numbers in the total cohort and within defined subgroups of patients. <h3>Results</h3> Data of 1327 RA patients treated with TNFα inhibitors and of 1276 patients treated with DMARDs were available for the analysis. There was a very good agreement between observed and expected rates of serious infections in the evaluation sample (see table). Of note, the agreement was also high in subgroups of patients with a higher risk of infections. <h3>Conclusions</h3> The evaluation of the RABBIT risk score for serious infections in individual patients showed high agreement between observed and expected rates of serious infections in an independent sample of RA patients. The agreement was also high for patients at high risk of infections. The RABBIT risk calculator is therefore useful for rheumatologists to identify patients at increased risk and avoid treatment combinations with a very high risk for serious infections. <h3>Acknowledgements</h3> Supported by a joint unconditional grant from Abbott, Amgen/Swedish Orphan Biovitrum, Bristol Myers Squibb, Essex/MSD, Pfizer, Roche, and UCB. <h3>References</h3> [1]Strangfeld A, Eveslage M, Schneider M, Bergerhausen HJ, Klopsch T, Zink A, Listing J. Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient? Ann Rheum Dis 2011; 70(11):1914-20. <h3>Disclosure of Interest</h3> None Declared
FRI0129 Differential performance of various cardiovascular risk calculators in predicting surrogate coronary outcomes in rheumatoid arthritis
Authors: G. A. Karpouzas, J. Malpeso, T. -Y. Choi, P. Nightingale, M. Budoff, G. Kitas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Various cardiovascular risk calculators predict future risk of incident events in the general population; an estimated risk&gt;10% is considered an “actionable” threshold for lifestyle and/ or pharmacologic intervention in the United States. The presence of coronary artery calcium (CAC&gt;0), high plaque burden (segment stenosis score- SSS&gt;5), and vulnerable plaque characteristics (low attenuation plaque, positive remodeling, spotty calcifications)- VP by coronary computed tomography angiography (CTA) may further optimize such risk predictions. <h3>Objectives</h3> To evaluate the performance of various risk calculators in predicting all 3 aforementioned surrogate coronary outcomes in patients with Rheumatoid Arthritis (RA). <h3>Methods</h3> One hundred and fifty RA subjects without symptoms or diagnosis of coronary artery disease underwent CTA; Qualitative and quantitative plaque evaluation was carried out using a standard 15- coronary segment American Heart Association Model. Cardiac risk scores were calculated using different iterations of Framingham (classic, NCEP-ATPIII, D’ Agostino), Reynolds, and QRISK2 calculators. An estimated risk threshold &gt;10% was used to predict CAC&gt;0, SSS&gt;5 and VP presence using Fisher’s exact tests. <h3>Results</h3> QRISK2 had the highest sensitivity (40%) in identifying RA subjects with actionable threshold, followed by D’Agostino (29.3%), classic Framingham and NCEP-ATPIII (both with 11.3%), and Reynold’s (2.7%). Risk score adjustment based on EULAR recommendations did not significantly alter the numbers of patients identified as actionable risk. Importantly, QRISK2 score &gt;10% performed superiorly to other calculators in predicting presence of coronary calcification, high plaque burden, and plaque with vulnerability characteristics (table). <h3>Conclusions</h3> QRISK2 most sensitively identifies RA subjects with &gt;10% risk for future cardiovascular event; at this cut-off, it has the highest performance of all calculators tested in identifying presence of coronary calcification, high plaque burden and vulnerable plaque features. <h3>Disclosure of Interest</h3> None Declared
P381The right atrioventricular pacemaker ring in the avian heart, myth or reality?
Authors: V Prosheva
Journal: Cardiovascular Research (2014)

Background: In the avian heart right atrioventricular (AV) valve there is a large, unicuspid, muscular flap, in remarkable contrast to the fibrous structure characteristic of the mammalian tricuspid valve. Histological studies showed that in addition to a sinus node, AV node, His bundle, left and right bundle branches, the birds also have the right AV Purkinje ring and a special middle bundle branch. The atrioventricular Purkinje ring is located in the atrial sheet of the AV muscular valve along all its base length. Purpose: To perform electrophysiological identification of cells on the atrial side of the chicken right muscular AV valve. Methods: Experiments were conducted on spontaneously contracting right muscular AV valve and contiguous atrial muscle preparations isolated from nine adult chicken hearts using the standard microelectrode technique. Results: The rate of spontaneous contractions of isolated preparations of muscular valve was 121 ± 7 beats/min. Three types of action potentials (APs) were registered from the atrial surface of the valve: APs of working myocardium cells, APs of pacemaker cells and APs of conducting cells. A working myocardium AP with a constant level of membrane potential during phase 4 was the most frequently recorded voltage waveform in the atrial surface of the muscular valve. Pacemaker APs have much lesser values of a maximum upstroke rate (4.3 ± 0.6 vs 193.9 ± 4.9 V/s), an amplitude (73.4 ± 1.7 vs 108.7 ± 1.0 mV ) but higher an amplitude of diastolic depolarization (7.7 ± 0.8 vs 1.4 ± 0.1 mV) than conducting APs (P<0.05). Conducting APs are usually registered from the part of the free edge of the valve, attached to the right ventricle free wall and also from the areas adjacent to dorsal and ventral sides of the interventricular septum. Detailed microelectrode mapping of APs in an isolated muscular valve preparation revealed the presence of the pacemaker zone on the valve atrial side which is permanently localized along the whole length of its base from ventral to dorsal attachment of the valve to the interventricular septum where the fibrous tissue is present. Conclusion: Our study provides evidence of the regularity of the course and the electrophysiological organization of the pacemaker zone in isolated chicken muscular valve. Location of found out pacemaker zone in the muscular valve coincide with histological description of topography of valve component of the right AV Purkinje ring. We believe that we have offered the proof that the avian right AV Purkinje ring is in reality the right AV pacemaker ring. This study was supported by the RFBR.
AB0421 Evolution of Fatigue in Rheumatoid Arthritis Treated with Rituximab: Table 1.
Authors: D. Chafia
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Fatigue is a common symptom of rheumatoid arthritis (RA), it can greatly affect the patient9s quality of life. Our study aimed to evaluate fatigue evolution and its correlation with the scalability parameters in RA patient9s naive to TNF blockers, treated with rituximab (RTX). <h3>Methods</h3> prospective observational study Including patients who fulfilled the ACR 1987 RA criteria and/or ACR/EULAR 2010 RA criteria, treated with rituximab (RTX), after conventional treatment failure. Patients were followed prospectively over a period of 06 months. Fatigue was assessed respectively before treatment (T0), after treatment at 3 months (T1), 6 months (T2) in all patients. We used the 10 mm visual analogue scale of the fatigue and the FACIT -F questionnaire (functional assessment of chronic illness therapy -fatigue). We assessed at the same time, DAS vs- 28, ESR and HAQ (Health Assessment Questionnaire). <h3>Results</h3> 28 patients were included, mean age: 51.17±10 years. The RA mean duration was 13.55±6.26 years. ACPA positive in 78%.Table 1 summarizes the values of various parameters (DAS28, HAQ, VAS fatigue, FACIT -F) measured respectively at T0, T1, and T2. At T0, all the patients reported a variable degree of fatigue. We noted a significant correlation between the rate of <i>DAS28</i> and <i>VAS fatigue</i> at <i>T0</i>, <i>T1</i> and <i>T2</i>, a significant correlation between <i>HAQ</i> and <i>VAS-fatigue</i> at <i>T0</i>, <i>T1</i>, <i>T2</i>. <h3>Conclusions</h3> In patients rheumatoid arthritis treated with RTX, fatigue improvement seems to be positively correlated with the disease activity and the quality of life. <h3>References</h3> I. Rupp, H.C. Boshuizen, C.E. J.H. Dimant and al.Impact of fatigue on health-related quality of life in rheumatoid arthritis. Arthritis Care Res. 51 (2004), pp4578-85. R. Caporali and al. Long term treatment of rheumatoid arthritis zith rituximab. Autoimmunity Reviews. Volume 8, June 2009, pages 591-94. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2478
EG-14 * EPIGENETIC DYSREGULATION OF THE HoxA LOCUS AND OTHER HOMEOBOX GENES DRIVEN BY Ink4a/arf DEFICIENCY AND EGFRviii
Authors: R. Salinas, J. Liu, R. Delgado, K. Y. Park, J. Price, A. Ramos, J. Phillips, D. Lim
Journal: Neuro-Oncology (2014)

It is increasingly clear that while genetic alterations drive glioblastoma development, epigenetic dysregulation can also contribute to oncogenesis. Although there is clear evidence of tumors driven by specific mutations to histones or their modifiers, genomic studies have demonstrated that the majority of brain tumors are not molecularly classified by mutations in key epigenetic regulators. We hypothesized that some of the most common genetic mutations in glioblastoma can lead to chromatin-based transcriptional dysregulation. First, to investigate the transcriptional changes from specific genetic mutations, we performed RNA-sequencing analysis of a mouse tumor progression model with Ink4a/arf−/- cells derived from the subventricular zone (SVZ) which do not form tumors when intracranially injected into SCID mice, "primary" tumors produced by overexpression of EGFRviii in Ink4a/Arf−/- cells, and "secondary" tumors that models tumor recurrence via reinjection of primary tumor cells into the brains of other mice. Compared to Ink4a/Arf-/-, both primary and secondary tumors downregulated genes related to neuron differentiation and cell adhesion, while overexpressing homeobox genes related to cellular morphogenesis, including the HoxA locus. Secondary tumors, which carry worse survival, upregulate invasion-associated extracellular matrix and basement membrane genes. Intriguingly, ChIP-seq analysis revealed a clear loss of the repressive H3K27me3 mark at the HoxA locus and other homeodomain containing genes upon Ink4a/Arf inactivation. Subsequently, a subset of the genes became overexpressed upon tumorigenesis with a concomitant and progressive increase of the promoter activating H3K4me3 mark. Furthermore, IHC in mouse and a subset of human samples demonstrated heterogeneity of H3K27me3 staining compared to H3, while Western blot analysis also demonstrated a relative decrease in HK27me3 staining in mouse tumor samples compared to Ink4a/Arf−/-. These results support a model whereby Ink4a/Arf deficiency is sufficient to induce epigenetic changes via loss of H3K27me3, generating heterogeneity within a given tumor sample and allowing for EGFRviii driven oncogenic selection.
Abstract 2535: PrevOnco® exhibits anti-tumor activity in <i>in vitro</i> and <i>in vivo</i> human tumor models: Combination therapy (PrevOnco® / Doxorubicin) demonstrates a better efficacy profile with enhanced survival rate in a liver cancer model
Authors: Francesca Incardona, Kevin Dines, Bassam Damaj, Richard Martin, Mohamed Hachicha
Journal: Cancer Research (2011)

Abstract Background: The investigational anti-neoplastic agent PrevOnco® (know as Prevacid® /Lansoprazole®) is entering Phase II clinical trials in the US for hepatocellular carcinoma. Objectives: This study examined the efficacy of PrevOnco® in both in vitro and in vivo human tumor models. The optimal oral formulation, pharmacokinetic parameters and its combination therapy with doxorubicin were evaluated. Methods: Cytotoxicity was assessed in vitro by MTT analysis. In vivo efficacy was assessed in nude mice in 2 survival models of the pediatric kidney-derived G401 and SR leukemia, and one ectotopic HepG2 model. Results: In MTT assays, PrevOnco® demonstrated a concentration-dependent cytotoxic effect against a number of cancer cell lines (MC116, HOP-62, MOLT4, HCT-15, JMI, RPMI6666, RS 1184, STA 486, SF539, U251, SF295, UACC-62). Synergistic activity was observed with doxorubicin but not with cisplatin. PrevOnco® was significantly more effective than Omeprezole or SCH-28080. Pharmacokinetic analysis in nude mice showed 10% PEG400 to be a better vehicle than carboxy-methyl cellulose. A mean maximum concentration (Cmax) of 20,242 ng/mL was detected at 0.5 hours (Tmax) with the mean dose adjusted area under the curve (AUC) determined to be 846.5 nM*hr/mg. The half life (T1/2) of the compound was 0.9 hours. PrevOnco® at 100 mg/kg given orally significantly prolonged the survival rate in the G401 kidney xenograft by 60% at day 70 whereas all mice in vehicle treaded group died. At study end (day 83) 26% of the mice remained alive in the treated group. SR leukemia xenograft treated with PrevOnco® survived through the end of the study with &amp;gt;80% of the mice remaining alive. PrevOnco® induced a dose-dependent reduction in tumor growth in hepG2 model. A synergestic antitumoral effect was obtained with the combination treatment of PrevOnco® at 30 mg/kg and doxorubicin at10 mg/kg. PrevOnco® levels in hepG2 tumors following 100 mg/Kg BID treatment for 3 consecutive days indicated accumulation of the drug into tumor tissue. Conclusion: PrevOnco® exhibited anti-neoplastic activity in both in vitro and in vivo, enhancing survival and inhibiting tumor growth. Synergistic activity was obtained with doxorubicin in xenograft model of liver cancer, suggesting a potential new combination therapy for the treatment of liver cancer with less toxicological liability. 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 2535. doi:10.1158/1538-7445.AM2011-2535
Ultrasound-Guided Insertion of a Radial Arterial Catheter
Authors: Jonathan Ailon, Ophyr Mourad, Vince Chien, Tomas Saun, Shelly P. Dev
Journal: New England Journal of Medicine (2014)

Ultrasonography helps to ensure safe and successful insertion of an arterial catheter. This video demonstrates the use of ultrasound guidance for radial arterial catheterization in adults with the over-the-needle approach in the transverse and longitudinal planes.
PATTERNS OF ASPIRIN UTILIZATION AND OUTCOMES AMONG PATIENTS WITH DIABETES MELLITUS: A PROPENSITY SCORE MATCHED ANALYSIS FROM THE SAVOR-TIMI 53 TRIAL
Authors: Nihar Desai, Benjamin Scirica, Philippe Steg, Darren McGuire, Ofri Mosenzon, Kelly Im, Itamar Raz, Eugene Braunwald, Deepak Bhatt
Journal: Journal of the American College of Cardiology (2016)
Rim Sign in Acute Cholecystitis
Authors: Seok Tae Lim, Myung-Hee Sohn
Journal: Clinical Nuclear Medicine (2002)

From the Department of Nuclear Medicine,* Institute for Medical Sciences,† and Research Institute of Clinical Medicine,‡ Chonbuk National University Medical School, Chonju, Korea Received for publication April 25, 2001. Accepted July 6, 2001. Supported by Korea Research Foundation grant KRF-99-041-F00273. Correspondence: Myung-Hee Sohn, Department of Nuclear Medicine, Chonbuk National University Medical School, 634-18 Keumam-dong Duckjin-gu, Chonju, Chonbuk 561–712, Korea. E-mail: [email protected] CLINICAL NUCLEAR MEDICINE publishes in each issue a section of references to articles of interest to its readers taken from the world medical literature. Articles below were selected from listings received through November 5, 2001. Slavic and Oriental language articles have English summaries unless marked with an asterisk after language abbreviation.
Abstract P1-01-13: Immediate Breast Reconstruction after Mastectomy in Invasive Breast Cancer: Identification of Patients Not Needing Postoperative Radiotherapy
Authors: AM Moorman, D de Leeuw, RLJH Bourez, NG Leeksma, EA. Kouwenhoven
Journal: Cancer Research (2010)

Abstract Background: Immediate breast reconstruction after ablative breast surgery is psychologically and cosmetically preferable above second stage reconstruction. Since postoperative radiotherapy strongly increases risk of implant loss, it is a challenge to select preoperatively those patients who do not need postoperative locoregional radiotherapy after breast reconstruction. Besides radicality of tumour resection, it would be helpful to accurate identify N0-1 positive patients preoperatively. Aim: Risk assessment of postoperative locoregional radiotherapy in breast cancer patients with preoperative negative axillary lymphnodes. Patients and Methods: During period January 2007-2010 478 consecutive primary breast cancer patients were analysed. Each patient had regular X-mammography and breast ultrasonography. Ipsilateral axillary ultrasonography was routinely performed in case of BIRADS 4, 5 or 6 status of the breast tumour. Suspected lymphnodes (thickness of cortex &amp;gt; 2.3mm) were analysed by cytology or histology. Sentinel node biopsies (SNB) were harvested after Scintigraphy and Patent Blue Dye injection. Pathologic examination of SNB were classified as macrometastais (2mm), micrometasasis (0,2-2mm), isolated tumour cells (&amp;lt;0,2mm). Complete axillary lymphnode dissection (ALD) was routinely performed when one micro-or macrometastasis was present in the SNB, according to the Dutch Guidelines. Results: Threehunderd fourty four patients had radiological unsuspected axillary lymphnodes (77.5%). Their tumour-status was cT1 (216), cT2 (68), cT3 (4). In all these 344 patients 82 micro-and macrometastasis were found in the first SNB. Secondary ALD showed ≥4 metastasis in 5 patients: One of these 5 patients had a cT1c tumour, two a cT2, and two had a tumour larger than 5 cm. Overall risk for ≥4 positive lymphnode in patients with radiological unsuspected lymphnode is (5/344) 1.5%. Based on cT-status the risk for ≥4 positive lymphnodes with radiological unsuspected lymphnodes is 1/216 (0.46%) for cT1, 2/68 (3%) for cT2, 2/4 (50%) for cT3 tumours, respectively . Conclusion: Risk for postoperative locoregional radiotherapy is minimal for cT1-2 breast cancer patients with preoperative radiological unsuspected axillary lymphnodes. Direct reconstruction after ablative therapy for these patients appears to be safe. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-13.
Perirenal, Peripelvic, and Upper Ureter Abscesses in a Nearly Nonfunctioning Kidney Demonstrated by Tc-99m DMSA and Ga-67 Renal SPECT
Authors: KAI-YUAN TZEN, TZU-CHEN YEN, KUN-JU LIN
Journal: Clinical Nuclear Medicine (1999)

A 38-year-old woman reported intermittent chills, fever, and left flank pain lasting for approximately 20 days. Radiographs showed bilateral staghorn calculi in the kidneys. Tc-99m DMSA and Ga-67 renal SPECT were performed to preclude the possibility of acute pyelonephritis. Tc-99m DMSA scintigraphy showed minimal uptake of DMSA in the left kidney, whereas Ga-67 renal SPECT showed intense uptake in the left perirenal area and left upper ureter. Surgery revealed abscesses in the left perirenal, left peripelvic, and left upper ureter. The left kidney was removed, and pus culture showed Escherichia coli and Proteus sp.