tbuckley/cabot-search huggingface dataset:
Abstract 2859: Identification of driver mutations in colon cancer using Sleeping Beauty mutagenesis
Authors: Timothy K. Starr, Raha Allaei, Aaron Sarver, Kevin Silverstein, M. Gerard O'Sullivan, Robert Cormier, David Largaespada
Journal: Cancer Research (2011)

Abstract Human colon tumors contain hundreds of genetic and epigenetic anomalies, of which only a handful are responsible for the growth and development of the tumor. We have developed a forward genetic screen in mice that can identify those mutations capable of causing gastrointestinal tract tumors. By comparing the mutations identified in our screen with those found in human colon tumors we can pinpoint the drivers of carcinogenesis. The forward genetic screen uses the Sleeping Beauty (SB) DNA transposon as a random mutagen capable of both activating and inactivating genes. Using Cre recombinase under the control of the Villin promoter we can selectively activate this mutagenesis in intestinal epithelial cells in the mouse. Tumors generated in these mice are analyzed for transposon insertion sites using linker mediated-PCR in combination with high-throughput sequencing. This analysis provides us with genomic sequence that can be mapped to the mouse genome. Candidate cancer driver genes are identified because they are located in areas of the genome that are recurrently mutated by the SB transposon in multiple tumors. We conducted the screen in wild-type mice and identified 77 candidate cancer genes, of which six were previously known human colon cancer genes (APC, BMPR1A, SMAD4, PTEN, FBXW7, CDK8). More importantly, we identified many novel candidate drivers that can now serve as potential targets in colon cancer therapy. We have extended our studies by conducting three more screens using mice that already contain a known driver mutation. The purpose of these new screens is to gain a better understanding of the genetic changes that cooperate with common mutations found in colon cancer. The three screens used mice that have a mutation in Apc (ApcMin), carry a dominant negative acting Trp53 (p53R270H), or are null for the tumor suppressor gene p19ARF. We have completed the screen in ApcMin mice and found an additional 30 candidate drivers of colon cancer that may specifically cooperate with the Apc mutation. The two final screens are in the process of completion and should uncover genes that cooperate with mutations in Trp53 and p19ARF. The results of these studies will greatly expand the list of potential therapeutic targets and will enhance our understanding of the genetic etiology of colon cancer. 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 2859. doi:10.1158/1538-7445.AM2011-2859
S90 The National Lung Cancer Audit – No Evidence of a “Seven-Year Itch”: Abstract S90 Table 1
Authors: P Beckett, MD Peake, I Woolhouse, R Stanley
Journal: Thorax (2012)

<h3>Introduction</h3> The National Lung Cancer Audit, now in its7<sup>th</sup> year, is run jointly by the Royal College of Physicians and The Information Centre for health and social care, and is commissioned by the Healthcare Quality Improvement Partnership (HQIP). Its development was driven by the realisation that lung cancer outcomes vary widely across the UK and are poor compared to other western countries. The aim of the audit is to facilitate service improvement by recording elements of process and outcomes in lung cancer on a large scale and, using case-mix adjustment, to explain the wide variations noted and improve standards of care. Although several other countries also submit data to the audit, this abstract presents provisional results for UK only. <h3>Results</h3> In this 7th year of data collection, 31,429 patient records were submitted, making it the most comprehensive annual dataset so far, with year on year improvements in the quality of the data on individual cases. Full details are given in Table 1. Whilst the histological confirmation rate has fallen slightly, it remains well above that recorded in early years. The surgical resection rate has risen and in those patients with NSCLC has gone above 20% for the first time. Almost 80% of patients benefit from the input of a specialist nurses, although in only 60% of cases is the nurse present at the time of diagnosis. Our final presentation will contain further analyses of survival across the audit lifespan. <h3>Conclusions</h3> This new data provides further evidence of rising standards of care in England, which in some cases now approach those quoted by other international groups. Far from seeing a "Seven Year Itch", the enthusiasm of lung cancer teams continues to produce cancer audit of a standard that is the envy of other groups both nationally and internationally. Major changes in the recording of cancer intelligence in England, such as the mandated Cancer Outcomes and Services Dataset (COSD), will have significant implications for the future role of the audit and work is ongoing to ensure that the data collected continues to be appropriate and relevant.
Effect of Amlodipine on Morbidity and Mortality in Severe Chronic Heart Failure
Authors: Milton Packer, Christopher M. O'Connor, Jalal K. Ghali, Milton L. Pressler, Peter E. Carson, Robert N. Belkin, Alan B. Miller, Gerald W. Neuberg, David Frid, John H. Wertheimer, Anne B. Cropp, David L. DeMets
Journal: New England Journal of Medicine (1996)

Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure.We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events.Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001).Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.
Evaluation of Tetracycline or Penicillin and Ampicillin for Treatment of Acute Pelvic Inflammatory Disease
Authors: F. Gary Cunningham, John C. Hauth, James D. Strong, William N. P. Herbert, Larry C. Gilstrap, Russell H. Wilson, Sheryl S. Kappus
Journal: New England Journal of Medicine (1977)

To evaluate guidelines for outpatient treatment of acute pelvic inflammatory disease recommended by the Center for Disease Control we studied 197 afflicted women. The women were treated either with tetracycline or with procaine penicillin and ampicillin, and 92% were subsequently seen at least once to assess efficacy of clinical and microbiologic treatment. Neisseria gonorrhoeae was isolated from the lower genital tract in 68% of these women, and although they had a quicker symptomatic response than those with nongonococcal infection (P less than 0.01), the two regimens were equally effective in producing clinical cure. However, subsequent identification of a pelvic abscess was 10 times more common in women from whom N. gonorrhoeae was not isolated. Therapy for pelvic inflammatory disease must be empirical since it is impossible to distinguish clinically between gonococcal and nongonococcal infection, and our data indicate that both regimens recommended by the Center for Disease Control are effective.
P4-12-01: The Breast-Activity and Healthy Eating after Diagnosis (B-AHEAD) Study – A Randomised Comparison of Weight Control Programmes during Adjuvant Treatment.
Authors: M Harvie, M Pegington, N Bundred, A Campbell, J Wolstenholme, J Adams, S Speed, J Morris, A Howell
Journal: Cancer Research (2011)

Abstract Background: Excess weight at diagnosis and weight gain during treatment are linked to increased mortality from breast cancer. Since 60% of breast cancer patients are overweight at diagnosis and 75% gain weight during treatment, weight control should improve outcome but the optimal intervention is unknown. Aim: To compare 3 programmes for weight control after surgery for primary breast cancer. Methods: We have recruited a randomised trial of 2 diet and exercise weight control interventions (1. a community based supervised group programme, 2. a mail and phone programme) compared to standard written advice (control). We are comparing the relative effects of the 3 programmes on body weight and composition (by dual energy x-ray absorptiometry), cardiovascular risk parameters (lipids, blood pressure), a marker of breast cancer prognosis (insulin resistance), fitness and quality of life over the first year after diagnosis. In total 409 women have been randomised (45% of eligible women) and 21 women have left the trial (5.1%), 357 have completed the 6 month assessments, all are due to complete the trial in December 2011. Results: Weight and body fat results at 6 months indicate that the low cost mail and phone programme is equal to the supervised programme and both are significantly superior to written advice, but not in patients receiving chemotherapy. The high uptake and adherence to the trial shows interest and motivation of a significant number of cancer patients to make positive changes to lifestyle at the time of diagnosis. The final trial results will be presented at the December meeting. This abstract presents independent research commissioned by the National Institute for Health Research under the Research for Patient Benefit programme. The views expressed here are those of the authors and not necessarily those of the funding organisations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-01.
PTH-125 Survival Following Intestinal And Multivisceral Transplantation At Addenbrooke’s Hospital, Cambridge, Uk
Authors: C Rutter, L Sharkey, A Butler, N Russell, C Pither, J Green, S Duncan, D Bond, B Chukualim, J Woodward, S Gabe, N Jamieson, S Middleton
Journal: Gut (2014)

<h3>Introduction</h3> Small intestinal transplantation (SBT) was first undertaken in the UK in Cambridge in 1991. Since the introduction of new immunosuppressive agents around the millenium, results have improved and we present our experience over the last 10 years. Since 2003, 47 tranplants have been performed on 43 patients. Grafts include small bowel or small bowel/colon (SBT), liver and small bowel (LSBT), modified multivisceral (MMVT – small bowel, stomach, pancreas, no liver) and multivisceral (MVT – intestine, stomach, pancreas and liver) transplantation. Cambridge is the only UK centre offering MVT in adults. <h3>Methods</h3> A review of all patients who underwent small intestine and multivsiceral transplantation at Addenbrooke’s Hospital between 2003 and 2013. Kaplan-Meier survival data are shown for each group of organs transplanted. <h3>Results</h3> Five year survival for all patients transplanted is 77%. Survival curves for each organ group transplanted is graphed below: <h3>Conclusion</h3> Five year survival in our patients transplanted since 2003 is 100% for SBT and LSBT and 65% for MVT, compared with international registry survival figures of 59% (SBT and LSBT combined) and 22% respectively. In recent years we have also experienced an increase in the number of urgent transplants performed and these patients are often critically unwell at the time of surgery. Our centre undertakes a relatively large number of procedures and this, coupled with a particular focus on multidisciplinary team working, may account in part for our favourable survival figures. <h3>Disclosure of Interest</h3> None Declared.
DOES A GOOD FUNCTIONAL CAPACITY (≥10 METS) ATENUATE THE EFFECTS OF AGING ON CARDIOVASCULAR RISK FACTORS? RESULTS FROM THE CARDIOVASCULAR RISK PROFILE FROM SUBJECTS OF ALL AGES ACCORDING TO FUNCTIONAL CAPACITY
Authors: Monica Acevedo, Giovanna Valentino, María José Bustamante, Veronica Kramer, Lorena Orellana, Marcela Adasme, Fernando Baraona, Carlos Navarrete
Journal: Journal of the American College of Cardiology (2016)
Ensuring Public Health Neutrality
Authors: Les F. Roberts, Michael J. VanRooyen
Journal: New England Journal of Medicine (2013)

Interview with Dr. Michael VanRooyen on threats to international public health work and the importance of medical neutrality. (12:16)Download In response to events in Pakistan that led to the deaths of eight vaccination workers and the suspension of polio-eradication efforts, deans of U.S. public health schools advocate refraining from disguising military or intelligence actions as public health activities.
Early Patterns of Sofosbuvir Utilization by State Medicaid Programs
Authors: Joshua M Liao, Michael A Fischer
Journal: New England Journal of Medicine (2015)

Noninvasive Positive-Pressure VentilationTo the Editor: Kelly et al. (June 4 issue) 1 list the complications associated with noninvasive positive-pressure ventilation (NPPV) and potential responses to such complications in Table 1 of the print supplement to their video.There are two other important complications that might have been included.Gastric insufflation is reported in up to 50% of patients receiving NPPV. 2 If a tense and tympanic abdomen develops and arterial oxygen saturation declines, gastric insufflation should be considered.A simple radiograph may reveal the presence of substantial air in the stomach or an elevated diaphragm. 3 The insertion of a nasogastric tube quickly relieves the symptoms.In addition, noninvasive ventilation can result in conjunctival irritation as a result of an air leak or direct irritation, particularly in patients with a poorly fitting nasal or oronasal mask.Refitting or reseating the mask generally corrects the problem.
FRI0013 Activation of the Non-Canonical NF-κB Pathway in Dendritic Cells Upregulates Extrathymic Autoimmune Regulator (AIRE) Expression
Authors: L.F.A. Huitema, B. Helder, A.-R. Noort, M.C. Lebre, L. Boon, F.G. Kroese, S.W. Tas
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> The nuclear factor (NF)-κB family of transcription factors has a key role in the regulation of inflammation. Ligation of CD40 on dendritic cells can induce early production of inflammatory mediators via the canonical NF-κB pathway, as well as late expression of the of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) via non-canonical NF-κB signalling [1]. Non-canonical NF-κB signalling via CD40 is also crucially important for the expression of Autoimmune Regulator (AIRE) in the thymus. AIRE is a transcription factor that is involved in thymic negative selection of autoreactive T cells and therefore is pivotal in the establishment of central tolerance. We have recently found extrathymic AIRE-expressing cells (eTACs) that may play a role in peripheral tolerance in rheumatoid arthritis synovial tissue and glandular tissue from Sjogren9s syndrome patients. eTACs are mainly antigen presenting cells, including DC, that can inactivate peripheral T cell responses. However, until now the stimuli that can induce extrathymic AIRE expression in DC are largely unknown. <h3>Objectives</h3> To study whether activation of the non-canonical NF-κB pathway stimulates AIRE expression in human monocyte-derived DC. <h3>Methods</h3> Monocyte-derived DC were generated by culturing healthy donor monocytes for 6 days with GM-CSF and IL-4. Maturation was induced by addition of LPS or the non-canonical NF-κB stimuli such as lymphotoxin, LIGHT, RANKL or anti-CD40 for 48 hours. <i>AIRE</i> and <i>IDO</i> expression was quantified by qPCR and cleavage of p100 into p52 was analyzed by Western blot. Presence of AIRE protein was analyzed by Western blot and immunofluorescence staining. <h3>Results</h3> Anti-CD40 and RANKL stimulation of DC resulted in cleavage of p100 into p52, upregulation of <i>AIRE</i> RNA and AIRE protein. Confocal microscopy revealed that AIRE protein was localised in the nucleus. Interestingly, this was accompanied by increased expression of the <i>IDO</i> in these cells. <h3>Conclusions</h3> CD40 and RANKL stimulation in DC activates the non-canonical NF-κB pathway and simultaneously upregulates <i>AIRE</i> and <i>IDO</i> expression. The functional significance of peripheral AIRE expression in DC requires further investigation, but it may be associated with immunoregulatory properties. Eventually, this knowledge may be exploited to develop new treatment modalities for patients with autoimmune diseases, including DC-based therapies. <h3>References</h3> Tas SW, Vervoordeldonk MJ, Hajji N, Schuitemaker JH, van der Sluijs KF, May MJ, et al. Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 2007;110:1540-9. <h3>Disclosure of Interest</h3> None declared
PTH-138 Tnf-a Dependent Angiopoeitin Mediated Angiogenesis In Sporadic Small Bowel Angiodysplasia; Novel Pathophysiology And Potential Clinical Marker: Abstract PTH-138 Table 1
Authors: G Holleran, B Hall, P Crotty, S Smith, D McNamara
Journal: Gut (2014)

<h3>Introduction</h3> Angiodysplasias account for over 50% of small bowel causes of obscure gastrointestinal bleeding. Angiodysplasias are thought to develop as a result of an imbalance in the angiogenic cascade, although the exact mechanism remains elusive. Previous research we have undertaken has associated elevated serum angiopoietin-2 (Ang-2) levels with angiodysplasia. Ang-1 and Ang-2 are ligands of the endothelial receptor tyrosine kinase Tie-2. Ang-1 regulates endothelial cell survival and blood vessel maturation and plays a key role in maintaining vascular integrity. Ang-2 is a functional antagonist of Ang-1. Inflammation and angiogenesis are associated with several pathological disorders and previous data suggests a TNF-α dependent dual functional roles of Tie2 in inflammatory angiogenesis <h3>Methods</h3> Following informed consent, serum samples were collected from patients with a definite diagnosis of sporadic small bowel angiodysplasia (P2) on capsule endoscopy, and from healthy controls in which GI bleeding had been out-ruled by a negative faecal immunochemical test. Serum levels of Ang-1, Ang-2 and TNF-α were measured using commercially available ELISA kits. All results were expressed as a mean and compared between patients and controls, and the mean of the ratio of ang2/ang1 levels for each group was calculated. <h3>Results</h3> A total of 80 samples were analysed for each factor, including 40 patients (48% male, average age 71 years) and 40 controls (43% male, average age 70 years). As expected and in keeping with our previous work levels of Ang-2 were significantly higher in patients (mean 4600 pg/ml) than in controls (mean 2973 pg/ml) p &lt; 0.001. In addition levels of Ang-1 were significantly lower in the patient group (mean 13071 pg/ml) vs. controls (mean 21169 pg/ml) p &lt; 0.004 (Table 1). We also found that levels of TNF-α were significantly lower in the patient group (mean 6.7 pg/ml) vs. controls (mean 12.2 pg/ml) p &lt; 0.003. The mean of the ratio of Ang2/Ang1 levels was found to be significantly higher in patients (1.05) vs. controls (0.29) p &lt; 0.05. <h3>Conclusion</h3> Ours is the first study to have identified a link between angiopoietin 1 and 2 ratios and gastrointestinal angiodysplasia. The TNF-α findings are also novel and would strongly suggest a role for inflammatory mediated angiogenesis in this condition. <h3>Disclosure of Interest</h3> None Declared.
AB0158 The z-score for the quantification of joint space narrowing in rheumatoid arthritis – a subanalysis of the lemeradix register -
Authors: A. Pfeil, J. Böttcher, K. Bornholdt, P. Oelzner, G. Wolf
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The reduction of finger joint space width in patients with rheumatoid arthritis (RA) is associated with joint damage and physical function loss of the finger joints which results in physical disability. <h3>Objectives</h3> The Z-Score is a new computer based technique to measure joint space reduction on hand radiographs in RA in a gender- and age-independent way. The aim of this study was to quantify longitudinal changes of joint space width by the Z-Score in comparison to the Sharp joint space narrowing score. <h3>Methods</h3> 94 RA-patients (68 women and 26 men) participating at the LEMERADIX REGISTER (Retrospective Comparison of Leflunomide and Methotrexate in Rheumatoid Arthritis by Digital Radiogrammetry (DXR) and Computer-aided Joint Space Analysis (CAJSA)) as a prospectively planned, comparative, multicenter retrospective study were included. 53 patients were treated with 15 mg methotrexate per week and 41 patients were treated with 10 mg leflunomide per day over an observation period of 1.8 years. Hand radiographs were acquired at baseline and after 1.8 years. The quantification of finger joint space width of the metacarpal-phalangeal articulations (MCP) was performed by the Z-score using the computer-assisted joint space analysis (Version 1.3.6; Sectra; Sweden) and the Sharp joint space narrowing score. <h3>Results</h3> For both treatment arms (leflunomide and methotrexate) no significant changes of the Sharp Erosion Score and Sharp joint space narrowing score were observed over the observation period of 1.8 years. The median Sharp joint space narrowing score of the first and second measurement was 1. For the methotrexate treated patients the Z-Score (MCP total) decreased (-0.13 SD) from 0.08 SD (initial measurement) to -0.05 SD (second measurement). Regarding, the leflunomide-group the Z-Score (MCP total) was not significantly reduced (-0.03 SD) from 0.16 SD (initial measurement) to 0.13 SD (second measurement). <h3>Conclusions</h3> In this longitudinal head to head comparison based on the LEMERADIX-Register the conventional scoring of the finger joint space width by the Sharp joint space narrowing score revealed no change of the median joint space width. The automatically quantification of the joint space width using the Z-Score was able to detect changes of finger joint space width in patient groups with different treatment arms. Consequently, the automatic quantification of finger joint space width by the Z-Score is a sensitive technique for the quantification of joint space reduction and treatment effects. <h3>Disclosure of Interest</h3> A. Pfeil Speakers bureau: speaker's fees from sanofi-aventis, J. Böttcher Speakers bureau: speaker's fees from sanofi-aventis, K. Bornholdt Employee of: full-time employee of Sanofi-Aventis Deutschland GmbH, Germany, P. Oelzner: None Declared, G. Wolf: None Declared