tbuckley/cabot-search huggingface dataset:
Abstract 1765: Inhibition of Notch signaling by a Notch1 monoclonal antibody induces robust anti-tumor efficacy in T-cell acute lymphoblastic leukemia and breast cancer
Authors: Ping Wei, Ming Qiu, Qinghai Peng, John Lippincott, Joseph Zachwieja, Eugenia Kraynov, Aidong Wu, Bora Han, Donna Stone, Wenwu Zhai, Isha Rymer, Jennifer Yang, Ketan Gajiwala, Xiu Yu, Yijie Gao, Lioudmila Tchistiakov, Wenxue Ma, Catriona H. M. Jamieson, Gerrit Los, Norman Greenberg, Kang Li
Journal: Cancer Research (2011)

Abstract Notch signaling is deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and advanced solid tumors, making it an attractive target for oncology drug development. In this present report, we describe a novel mouse monoclonal antibody, Notch1 mAb, that specifically binds to the negative regulatory region (NRR) of human Notch1 receptor. Using a T-ALL cell line, HPB-ALL, that harbors mutations in Notch1 heterodimerization and PEST domains, we demonstrated that Notch1 mAb blocked Notch signaling by reduction of Notch1 intracellular domain (NICD) and down-regulation of Notch target genes, Hes-1 and cMyc. Notch1 mAb caused cell growth inhibition of HPB-ALL and several other T-ALL cell lines, via induction of cell cycle arrest and apoptosis. Notch1 mAb treatment resulted in robust NICD reduction and marked antitumor efficacy in HBP-ALL xenograft model. Additional mechanism-of-action studies revealed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the anti-tumor activity of Notch1 mAb may be mediated by its direct effects on tumor cell growth or survival. Furthermore, this antibody led to a significant reduction in leukemia progenitor cells (LPCs) baring NOTCH1 mutation in bioluminescent humanized T-ALL LPC mouse models. In addition to its inhibitory effect on mutant Notch1, Notch1 mAb also displayed robust neutralization activity on wild type Notch1 and caused tumor growth inhibition in breast cancer models MDA-MB-231 and MX-1 by targeting the wild type receptor in these tumor types. Interestingly, using a gamma secretase inhibitor PF-03084014, we showed that Notch1 mAb and PF-03084014 elicited similar degree of biology responses in HPB-ALL cells. Our results indicate that antibodies that bind to NRR can act as potent inhibitors of Notch1 signaling and provide opportunities for development of novel cancer therapeutics for T-ALL and solid tumors. 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 1765. doi:10.1158/1538-7445.AM2011-1765
Response of 1α,25-Dihydroxyvitamin D<sub>3</sub>to Hypocalcemia in Human Subjects
Authors: John P. Bilezikian, Robert E. Canfield, Thomas P. Jacobs, Janet S. Polay, Ann P. D'Adamo, John A. Eisman, Hector F. DeLuca
Journal: New England Journal of Medicine (1978)

We determined the response of 1alpha,25-dihydroxyvitamin D3 after mithramycin-induced hypocalcemia in eight subjects with polyostotic Paget's disease of bone. Thirty-six hours after infusion of mithramycin (25 microgram per kilogram), the average calcium declined from 9.9 +/- 0.14 (S.E.M.) to 8.0 +/- 0.19 mg per deciliter (P less than 0.005). Serum parathyroid hormone increased from 122 +/- 6 to 226 +/- 36 microliter eq per milliliter (P less than 0.05), serum phosphate decreased from 3.8 +/- 0.11 to 2.9 +/- 0.14 mg per deciliter (P less than 0.005), and urinary cyclic 3,5'-adenosine monophosphate increased from 4.6 +/- 0.35 to 7.5 +/- 0.80 mumol per gram of creatinine (P less than 0.005). Serum 1alpha25-dihydroxyvitamin D3 rose from 98 +/- 12 to 332 +/- 61 pM (P less than 0.05), the increase following the changes in parathyroid hormone and phosphate by 12 to 24 hours. When this lag period was taken into account, there was a significant relation (P less than 0.01) between the increase in 1alpha,25-dihydroxyvitamin D3 and changes in parathyroid hormone (correlation coefficient, r = +0.91) and phosphate (r = -0.96). The relatively rapid response of 1alpha,25-dihydroxyvitamin D3 to hypocalcemia occurs with a time course consistent with regulation by parathyroid hormone and phosphate.
GP practices face CQC fee hikes of £2000 a year
Authors: Anne Gulland
Journal: BMJ (2016)

GPs have responded angrily to increases in the fees charged by the Care Quality Commission (CQC) which will see some single site practices paying more than £2000 extra a year.1

Under the new fee structure for 2016-17, a single site GP practice with up to 5000 patients would see its fees increase from £616 in 2015-16 to £2187 a year; a GP practice with 5001 to 10 000 patients would see fees go up from £725 to £2574; a practice with 10 001 to 15 000 patients would see a jump in fees from £839 to £2978; and a practice with more than 15 000 patients would see a hike of …
VARIABILITY OF ANTIPLATELET EFFECT WITH TICAGRELOR VERSUS CLOPIDOGREL IN DIABETIC PATIENTS
Authors: Mohammad Urooj Zafar, Sanja Mehremic, Carlos Linares Koloffon, Ayna Orazgurbanova, Usman Baber, Valentin Fuster, Juan Badimon
Journal: Journal of the American College of Cardiology (2016)
Gastrointestinal varicella zoster infection. Dissemination or reactivation of a latent virus in the gut?
Authors: D. Dado, I. Chernev
Journal: Endoscopy (2013)

Varicella zoster virus (VZV) is an exclusively human, highly neurotropic herpes virus that can present as two different clinical entities. The primary infection causes varicella, or chicken pox, while reactivation of the latent VZV causes herpes zoster, also known as shingles. It is less well known that the gastrointestinal system may be commonly affected by VZV infection and produces a variety of clinical symptoms. The pathogenesis of gastrointestinal involvement remains controversial. Recently, we read with interest two articles published in Endoscopy. One was written by Remmerswaal et al. and the other by Krones et al. [1] [2]. Both articles described cases of "disseminated" VZV infection of the gastrointestinal system. We would like to comment on a few aspects regarding the pathogenesis of gastrointestinal VZV infection and these two cases in particular.
FRI0428 Anti –tnf-a therapy and arterial stiffness in anklosing spondylitis; results with long-term 2 year- follow-up
Authors: E. çapkin, M. Karkucak, A. Kırıs, M. Şahin, A. Kucukali turkyılmaz, A. Karaca, F. Gökmen, A. Ayar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Anti-TNF-α are effectively used in management of AS, a chronic disease with increased risk of future cardiovascular events, but influence and additional benefit of these agents on arterial stiffness, a potentially modifiable risk marker for cardiovascular events, is controversial. <h3>Objectives</h3> Our aim was to evaluate the long term effectiveness on arterial stiffness [pulse wave velocity (PVW)] treated anti-TNF alpha treatment in AS. Our initial follow-up (24 week) study on the effectiveness of anti-TNF-α therapy on arterial stiffness in AS did not demonstrate any clear benefit, and since optimal follow-up period for observing this effect remains unknown we aimed to document further follow-up of these patients at 2 years. <h3>Methods</h3> A total 28 active AS patients (21 male, 7 female) were enrolled before initiation of biological therapy and their mid-term (24 weeks) evaluation was reported. For further evaluation initially reported patients were contacted 2 years after anti-TNF-α therapy, and arterial stiffness was assessed by using PWV <h3>Results</h3> After 2 year of anti-TNF-α therapy, despite significant improvements in patients' symptoms and clinical activity parameters including BASDAI score, erythrocyte sedimentation rate and C-reactive protein (p=0.001, p=0.015, p=0.001, respectively) no significant change was obtained in arterial stiffness parameters (7.9 ± 1.3 meter/second, 7.7 ± 1.3 meter/second and 8.3 ±1.1 meter/second, p=0.620). <h3>Conclusions</h3> In parallel with the previous 24-week evaluation, results at 2-year follow-up time point indicates that anti-TNF-α therapy does not improve arterial stiffness in patients with AS. <h3>References</h3> Arnett FC. Ankylosing Spondylitis. In: Koopman WJ, ed. Arthritis and Allied Condition. Philadelphia: Lippincott Williams and Wilkins, 2001:1317. Karkucak M, Cakırbay H, Capkın E, Topbaş M, Güler M, Tosun M, et al. The prevalance of ankylosing spondylitis in the eastern Black Sea region of Turkey. Eur J Gen Med 2011;8 (1):40-5. Capkın E, Kıris A, Karkucak M, Durmuş I, Gökmen F, Cansu A, et al. Investigation of effects of different treatment modalities on structural and functional vessel wall properties in patients with ankylosing spondylitis. Joint Bone Spine 2011;78(4):378-82. Capkın E, Karkucak M, Kırıs A, Durmus I, Karaman K, Karaca Aet al. Anti-TNF Alpha therapy may not ımprove arterial stiffnes ın patients with ankylosing spondylitis: 24 weeks-follow up. Rheumatology (oxford) 2012; 51(5):910-4. <h3>Disclosure of Interest</h3> None Declared
AB0377 Efficacy of tacrolimus combination therapy during the maintenance phase of systemic lupus erythematosus
Authors: K. Otsuka, Y. Miwa, M. Umemura, H. Tsukamoto, T. Tokunaga, H. Furuya, R. Yanai, S. Isojima, K. Wakabayashi, N. Yajima, T. Kasama
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In Japan, a placebo-controlled clinical trial of tacrolimus for lupus nephritis was performed to investigate the efficacy and safety of this agent. Based on the results obtained, administration of tacrolimus at an oral dose of 3 mg/day was approved for the treatment of lupus nephritis. <h3>Objectives</h3> The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) combination therapy during the maintenance phase of systemic lupus erythematosus (SLE). TAC was added to the existing therapy if the clinical symptoms worsened and/or if there was a decrease in the serum complements titer because it allowed for a decrease in the dose of prednisolone (PSL). <h3>Methods</h3> From 2009 to 2012, 38 patients were included in the study period for 1 year. TAC combination therapy (dosage range: 1 mg to 5 mg once daily) was given if there was worsening of any mild manifestations of active SLE, such as arthritis, skin eruptions, or asymptomatic nephritis, and/or if there was a decrease in the serum complement titer (C3c). This study reviewed the SLE Disease Activity Index (SLEDAI) score, the dosage of PSL, the serum levels of C3c, the anti-dsDNA titers and proteinuria. <h3>Results</h3> Twenty-eight patients were treated with TAC combination therapy and showed symptom improvement with the following results: 1) the dosage of PSL was reduced from 11.7 ± 5.6 to 8.2 ± 4.2 (mg/day) (P&lt;0.001), 2) the serum C3c concentration increased from 74.7 ± 21.9 to 86.4 ± 17.8 (mg/dl) (P=0.006), 3) the anti-dsDNA titer decreased from 39.6 ± 68.0 to 24.8 ± 49.1 (U/ml) (P&lt;0.001) and 4) the SLEDAI score improved from 6.2 ± 3.7 to 2.6 ± 2.3 (P&lt;0.001). Of note, the components of the SLEDAI with the greatest levels of improvement included headache (decreased from 7 patients to 1 patient), arthritis (from 3 patients to no patients), rash (from 6 patients to 2 patients), alopecia (from 5 patients to no patients), mucosal ulcer (from 2 patients to no patients) and fever (from 5 patients to 1 patient). Although the occurrence of proteinuria decreased from 46.0 ± 95.7 to 30.7 ± 74.2 (mg/dl) upon administration of TAC combination therapy, the difference was not significant (P=0.23). However, 8 patients treated with TAC combination therapy did not show disease improvement nor had worsening SLE. In addition, 2 patients discontinued therapy due to an adverse effect: muscle cramp or rhabdomyolysis. No patients presented abnormal urinalysis, progression to renal failure, or became a candidate for dialysis therapy. <h3>Conclusions</h3> TAC combination therapy was clinically useful in the maintenance phase of SLE. <h3>Disclosure of Interest</h3> None Declared
Abstract 1809: Reversal of Taxol resistance in ovarian cancer cell lines by IGF pathway inhibition
Authors: Jurriaan Brouwer-Visser, Susan Band Horwitz, Gloria S. Huang
Journal: Cancer Research (2010)

Abstract Our group recently reported increased insulin-like growth factor 2 (IGF2) expression and AKT activation in ovarian cancer cells following treatment with the microtubule-stabilizing agent Taxol. We hypothesized that IGF2 is a modulator of Taxol resistance. Therefore, we developed cell line models of Taxol-resistance in A2780 and HEY, two ovarian cell lines, by repeated treatment with increasing Taxol concentrations, with or without concurrent verapamil, a p-glycoprotein inhibitor. The involvement of IGF2 in drug resistance was evaluated by real time PCR, immunoblotting, siRNA knockdown of IGF2, and small-molecule inhibition of the IGF1 Receptor (IGF1R; which is the major receptor for IGF2). In both of the resistant cell lines (A2780-Tx8Vp, 3-fold Taxol-resistance; and HEY-T30, 40-fold Taxol-resistance), IGF2 mRNA expression, measured by real time PCR, was significantly elevated compared with the parental cell lines, while IGF1R expression, assessed by immunoblotting, was mildly decreased. IGF1R inhibition by the small molecule NVP-AEW541 dramatically re-sensitized both resistant cell lines to Taxol, and cell cycle analysis demonstrated that concurrent NVP-AEW541 and Taxol significantly enhanced G2/M arrest, compared with Taxol alone. While A2780-Tx8Vp cells did not express detectable mdr1/abcb1 (encoding p-glycoprotein), HEY-T30 cells did over-express mdr1 (and were sensitized to Taxol treatment by verapamil). To exclude a possible interaction with p-glycoprotein, we evaluated IGF2 siRNA as an alternate, more specific approach of targeting the IGF pathway in HEY-T30 cells. It was found that IGF2 depletion by siRNA significantly enhanced the antiproliferative effect of Taxol in these cells. In summary, IGF2 modulates Taxol resistance in these ovarian cancer cell lines. IGF pathway inhibition, by IGF2 depletion or by inhibition of its major receptor IGF1R, reverses Taxol resistance in these cells. Such novel findings suggest that IGF2 could be a therapeutic target for ovarian cancer, particularly in the setting of Taxol resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1809.
AB0771 The Use of Multi-Parametric MRI to Identify Synovitis in Patients with Osteoarthritis of the Knee without the Use of A Contrast Agent
Authors: C. Burnett, A.C. Redmond, A.-M. Keenan, A. Grainger, J.P. Ridgway, R. Hodgson
Journal: Annals of the Rheumatic Diseases (2014)

Cyanobacterial blooms found in freshwater systems are a source of environmental toxins that impact the immune system. Geitlerinema sp., a strain of cyanobacteria, produces toxins including lipopolysaccharide (LPS) which induces fever and potential respiratory disease. One mechanism of respiratory disease and inflammation is through the inhalation of LPS that is associated with neutrophil infiltration of the lungs. Based on our previous data that Geitlerinema sp. induces pro-inflammatory cytokines, we hypothesized that inhalation of Geitlerinema sp. LPS would induce lung inflammation in vivo. To address this hypothesis, c57Bl/6 mice were intranasally exposed to Geitlerinema sp. LPS before lungs and BAL fluid were assessed for inflammation and inflammatory markers 24 hours later. Our data show that inhalation of Geitlerinema sp. LPS induced lung inflammation by recruiting neutrophils into the airways. The data also demonstrate that Geitlerinema sp. LPS induces proinflammatory cytokines and chemokines: IL-6, IL-8, IFN-g, RANTES and TNF-a in the BAL fluid. Additionally, in vitro data using an airway epithelial cell line show that Geitlerinema sp. LPS induced production of pro-inflammatory cytokines is dependent on the NF-κB pathway. These data help to better understand the mechanism of Geitlerinema sp. LPS airway-induced inflammation and implicates the importance of the toxin in promoting human disease near freshwater ecosystems where cyanobacteria bloom.
Social and Economic Consequences of Overweight in Adolescence and Young Adulthood
Authors: Steven L. Gortmaker, Aviva Must, James M. Perrin, Arthur M. Sobol, William H. Dietz
Journal: New England Journal of Medicine (1993)

Overweight in adolescents may have deleterious effects on their subsequent self-esteem, social and economic characteristics, and physical health. We studied the relation between overweight and subsequent educational attainment, marital status, household income, and self-esteem in a nationally representative sample of 10,039 randomly selected young people who were 16 to 24 years old in 1981. Follow-up data were obtained in 1988 for 65 to 79 percent of the original cohort, depending on the variable studied. The characteristics of the subjects who had been overweight in 1981 were compared with those for young people with asthma, musculoskeletal abnormalities, and other chronic health conditions. Overweight was defined as a body-mass index above the 95th percentile for age and sex.
Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an open-label, randomised controlled trial
Authors: Henning Kelbæk, Dan Eik Høfsten, Lars Køber, Steffen Helqvist, Lene Kløvgaard, Lene Holmvang, Erik Jørgensen, Frants Pedersen, Kari Saunamäki, Ole De Backer, Lia E Bang, Klaus F Kofoed, Jacob Lønborg, Kiril Ahtarovski, Niels Vejlstrup, Hans E Bøtker, Christian J Terkelsen, Evald H Christiansen, Jan Ravkilde, Hans-Henrik Tilsted, Anton B Villadsen, Jens Aarøe, Svend E Jensen, Bent Raungaard, Lisette O Jensen, Peter Clemmensen, Peer Grande, Jan K Madsen, Christian Torp-Pedersen, Thomas Engstrøm
Journal: The Lancet (2016)
Abstract 4708: Preclinical development of an anti-miR-21 compound for hepatocellular carcinoma
Authors: Eric G. Marcusson, Asha Balakrishnan, Aaron N. Chang, Balkrishen Bhat, Andrei Goga
Journal: Cancer Research (2011)

Abstract micro-RNA-21 is frequently over-expressed and has been shown to correlate with poor outcome in multiple cancer types. Its genomic locus is amplified in some cancer types and miR-21 is also transactivated by several known cancer drivers (e.g. STAT3 and Ras). We have used a publically available data set from 86 patients to show that miR-21 is over-expressed in hepatocellular carcinoma (HCC). The treatment options for HCC are limited, thus making it the third leading cause of cancer related deaths worldwide. Additional treatments for HCC are greatly needed. We investigated the therapeutic potential of inhibiting miR-21 with chemically modified oligonucleotides known as anti-miRs using models of HCC, including a genetically engineered mouse model of HCC driven by an inducible, activated form of Ras. Short term treatment with the anti-miR led to a reduction in tumor formation. Furthermore, inhibition of miR-21 was clearly demonstrated by analysis of genome wide mRNA expression data from treated versus untreated tumors. This data showed that genes containing the mir-21 octamer sequence were the most significantly over-enriched among up-regulated genes compared to all of the other 65,535 possible octamers. We also determined the effect of long-term anti-miR-21 treatment on the survival in this mouse model of HCC. anti-miR-21 treated mice demonstrated a highly significant survival advantage (p&amp;lt;0.0001) over saline and control anti-miR treated mice. Our findings suggest that miR-21 is a promising candidate for the therapeutic intervention of liver cancer and further highlights the potential of anti-miR-mediated inhibition of microRNAs. 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 4708. doi:10.1158/1538-7445.AM2011-4708
Safety and efficacy of sorafenib in stella study, a Multicenter, Observational, Phase IV Study In Italian Centers
Authors: G.G. Di Costanzo, R. Sacco, G. de Stefano, V. Montesarchio, G. Cabibbo, T. Zolfino, P. Carucci, S. Pisconti, F. De Vita, P. Giovanis, A.F. Attili, C. Erminero, T. Fontana, B. Daniele
Journal: Annals of Oncology (2015)
Bladder-to-Duodenal Stump Reflux Simulating a Urinoma in a Patient With Renal and Pancreaticoduodenal Transplantation
Authors: CHUN K. KIM, DANIEL F. WORSLEY
Journal: Clinical Nuclear Medicine (1996)

Renal scintigraphy is a valuable tool in the evaluation of renal transplant complications, particularly surgical complications such as urine leak. The authors report a renal scan performed to rule out a urine leak, in a patient with renal and pancreaticoduodenal transplantation, which demonstrated reflux of urine from the bladder into the duodenal stump, simulating a urinoma.
PWE-065 Colonoscopy and Biopsy Practice in Patients with Diarrhoea
Authors: M I Haq, S Shah
Journal: Gut (2013)

<h3>Introduction</h3> Colonoscopy is often performed in patients undergoing investigation for unexplained diarrhoea. Obtaining colonoscopic biopsies for persistent diarrhoea is an auditable JAG standard. The aims of this audit were (1) To determine the diagnostic yield of colonoscopy in patients undergoing investigation for diarrhoea. (2) To determine the rate at which biopsies are undertaken in patients with a “normal” colonoscopy. (3) To assess for variations in biopsy sampling amongst endoscopists. <h3>Methods</h3> An analysis was performed of all colonoscopies with the indication of diarrhoea, undertaken in 2010. Interrogation of the electronic endoscopy reporting tool, looked at endoscopist discipline, findings at endoscopy, if biopsies were taken, number of biopsies and biopsy sites, and corresponding histology results. <h3>Results</h3> A total of 609 patients were identified in whom the indication for colonoscopy was diarrhoea. The mean age was 57 years (range 14–90 years) with 40.4% male and 59.6% female. Caecal intubation was achieved in 565 patients (92.8%) with terminal ileal intubation recorded in 231/609 patients (37.9%). Overall, biopsies were taken in 545/609 patients (89.5%). The median number of biopsies taken per procedure was 10.5 (range 1 – 22), with a median number of 5.5 from the left side of the colon and 4 from the right side. Colonoscopic appearances were abnormal in 295/609 (48.4%) patients with isolated proximal disease in 36/295 (12.2%). The most common endoscopist abnormality was diverticular disease in 149 patients (24.4% overall), followed by polyps in 115 (18.8%), suspected inflammation in 67 (11%), suspected tumour/cancer in 11 (1.8%), and melanosis coli in 1 patient (0.2%). Of the patients with suspected mucosal inflammation, histology revealed features of IBD in 25 (4.1%) of patients with isolated right-sided inflammation in 5 (0.8%) and terminal ileum alone in 2 (0.32%). Of the 609 colonoscopies, 261 (42.9%) were referred as a 2-week wait urgent suspected cancer referral, yet a diagnosis of cancer was made in only 4 cases (1.53%). Of the 7 cancers detected, 6 (85.7%) were located in the left colon. Of the 314 «normal» colonoscopies, biopsies were taken in 268 (85.4%) patients and histology confirmed microscopic colitis in 15 (4.77%) and mucosal inflammation in 27 (8.6%). There was variation in the frequency and number of biopsy specimens obtained: GI physicians 91.59% (median number 10.5), GI surgeons 84.39% (median number 8.5), Nurse/GP Endoscopist 92.45% (median number 8) and non-GI physicians/surgeons 92.8% (median number 5). <h3>Conclusion</h3> Although abnormal findings are not uncommon in patients undergoing colonoscopy for symptoms of diarrhoea, yield for cancer is low. There is variation in practise among endoscopists in obtaining biopsy samples in the setting of diarrhoea and normal colonoscopy <h3>Disclosure of Interest</h3> None Declared.