tbuckley/cabot-search huggingface dataset:
Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E
Authors: Cailin E. Joyce, Adrienne G. Yanez, Akihiro Mori, Akinori Yoda, Johanna S. Carroll, Carl D. Novina
Journal: Cancer Research (2016)

Abstract Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here, we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell-cycle proteins that could explain the antiproliferative effects in vitro. Using clinical specimens, we correlate the common cell-cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5′UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3′UTR. Moreover, their divergent effects occur through the 5′UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions. Cancer Res; 77(3); 613–22. ©2016 AACR.
Fast and Accurate Estimates of Divergence Times from Big Data
Authors: Beatriz Mello, Qiqing Tao, Koichiro Tamura, Sudhir Kumar
Journal: Molecular Biology and Evolution (2016)

Ongoing advances in sequencing technology have led to an explosive expansion in the molecular data available for building increasingly larger and more comprehensive timetrees. However, Bayesian relaxed-clock approaches frequently used to infer these timetrees impose a large computational burden and discourage critical assessment of the robustness of inferred times to model assumptions, influence of calibrations, and selection of optimal data subsets. We analyzed eight large, recently published, empirical datasets to compare time estimates produced by RelTime (a non-Bayesian method) with those reported by using Bayesian approaches. We find that RelTime estimates are very similar to Bayesian approaches, yet RelTime requires orders of magnitude less computational time. This means that the use of RelTime will enable greater rigor in molecular dating, because faster computational speeds encourage more extensive testing of the robustness of inferred timetrees to prior assumptions (models and calibrations) and data subsets. Thus, RelTime provides a reliable and computationally thrifty approach for dating the tree of life using large-scale molecular datasets.
OC-027 Use of Buccal Vitamin D Supplementation in Patients with Short Bowel Syndrome
Authors: GJH Thomson, C Mountford, N Thompson
Journal: Gut (2016)

<h3>Introduction</h3> Vitamin D (vit D) deficiency is a common consequence of short bowel syndrome and can detrimentally affect bone and muscle health. Oral vit D supplements can be absorbed variably and parenteral supplementation does not always result in improved serum levels.<sup>1</sup> We wished to see if buccal vit D supplementation represents a useful alternative? <h3>Methods</h3> Patients with short bowel syndrome who had not responded to high dose oral vit D supplementation and were prescribed buccal vit D spray ("Dlux3000" BetterYou<sup>(<b>TM</b>)</sup>) were identified through the regional nutrition service (n = 13). This cohort was 46.2% female and 53.8% male with a mean age of 52.7 years. Accurate measurements of all participants small bowel functionality were not available, however, 7 were recorded as having less than 100 cm of small bowel remaining. Not all participants were reliant on parenteral nutrition (n = 7), those who were(n = 6) received between 10 and 15 L parenteral nutrition per week. Participants were prescribed between 3000 and 9000 iu/day. 25(OH) vit D was used to measure vit D status. Baseline levels were obtained prior to when buccal vit D was prescribed. This was compared with the level obtained at their next clinic appointment, at least one month later. For analysis a paired t test was undertaken in two groups; A, including (n = 13), and B excluding (n = 8), patients using other vitamin D supplements concurrently. Of those in group B 75% had previously been prescribed oral vit D supplements without achieving vit D sufficiency. <h3>Results</h3> Group A: Mean baseline 25(OH)D was 22.3 ng/ml, 95%CI (18.1,26.5) (. Buccal vit D supplementation increased this to an average of 61.4 ng/ml, 95%CI (44.7, 78.1). This increase proved to be statistically significant (p =&lt; 0.05) and suggests that buccal vit D either alone or as an adjunct to oral supplements produces a significant rise in vit D level from that of deficiency to sufficiency. Group B: Mean baseline 25(OH)D was 21.9 ng/ml, 95%CI (18.3, 25.4). Using buccal vit D spray alone mean 25(OH)D was increased to 53 ng/ml, 95%CI (43.2, 62.8) (p =&lt; 0.05). This suggests that buccal vit D monotherapy may be sufficient to achieve adequate vit D levels in those patients who have not responded to oral supplements. <h3>Conclusion</h3> This study provides preliminary evidence from a small number of patients that buccal vit D spray may be an effective adjunct to oral vit D supplementation or be an effective monotherapy in short bowel patients who do not respond adequately to oral supplements. Further investigation into buccal vit D spray is warranted. <h3>Reference</h3> 1 Thacher TD, Clarke BL. Vitamin D insufficiency. <i>Mayo Clin Proc</i> 2011;<b>86</b>(1):50–60. http://doi.org/ 10.4065/mcp.2010.0567 <h3>Disclosure of Interest</h3> G. Thomson: None Declared, C. Mountford: None Declared, N. Thompson Conflict with: BSG secretary
Allogeneic Stem Cell Transplantation for Core Binding Factor Alpha-Positive Adult Acute Myelogenous Leukemia with a Reduced Intensity Conditioning Regimen Consisting of Intravenous Busulfan, Fludarabine, and 400 cGy Total Body Irradiation
Authors: Heeje Kim, Woo-Sung Min, Byung-Sik Cho, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Jong-Wook Lee, Chun-Choo Kim
Journal: Blood (2008)
SAT0223 Soluble Semaphorin 3A and Neuropilin-1: New Markers for Dysregulation of Angiogenesis in Systemic Sclerosis?
Authors: A. Olewicz-Gawlik, D. Sikorska, W. Samborski
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Semaphorins, through interactions with their receptors- neuropilins, play critical roles in many biological processes such as the regulation of immunity, apoptosis, cell migration and angiogenesis. Systemic sclerosis (SSc) is an autoimmune disease, characterised by dysregulation of angiogenesis, leading to severe ischemia and loss of capillaries. <h3>Objectives</h3> The aim of the study was to investigate if soluble semaphorin 3A and neuropilin-1 could be involved in the dysregulation of angiogenesis in systemic sclerosis. <h3>Methods</h3> This was an investigator-initiated cross-sectional study. Serum samples obtained from 37 patients with systemic sclerosis (age 53 ± 9 years) and control serum samples obtained from 24 healthy individuals (age 51 ± 15 years) and 20 patients with Sjögren9s syndrome (age 46 ± 9 years). Samples were analyzed for the presence of soluble semaphorin 3A and neuropilin-1 using enzyme-linked immunosorbent assays. The results were expressed as median and range and compared by Mann-Whitney U test. P≤0.05 were considered statistically significant. <h3>Results</h3> Serum semaphorin 3A levels were significantly higher in patients with systemic sclerosis (median 1.81 ng/mL; range 0.43–4.72 ng/mL) versus healthy controls (median 0.21 ng/mL; range 0.16–0.28 ng/mL) (p&lt;0.001). Neuropilin-1 levels were significantly increased (median 844.26 pg/mL; range 556.80–1271.54 pg/mL) in comparison to those detected in healthy controls (median 58.60 pg/mL; range 33.75–80.00 pg/mL) (p&lt;0.001) and patients with Sjögren9s syndrome (median 278 pg/mL; range 137.50–443.70 pg/mL) (p&lt;0.001). There was tendency to higher values of neuropilin-1 in patients with long lasting illness (Spearman9s; r=0.29, p=0.075). <h3>Conclusions</h3> Our data show that semaphorin 3A and neuropilin-1 levels are significantly increased in patients with systemic scleroderma. Semaphorin 3A and neuropilin-1 may be involved in the modifications of neuro-vascular mechanisms leading to dysregulation of angiogenesis in systemic scleroderma. <h3>Disclosure of Interest</h3> None declared
Discovering and Developing Successful Cardiovascular Therapeutics
Authors: James N. Topper, John D. Rutherford
Journal: Circulation (2016)

Dr James (also known as Jamie) N. Topper, MD, PhD, serves as Managing General Partner at Frazier Healthcare Partners, where he leads the Life Science Venture practice. In 2011, and 2016, he was named to the Midas List of leading venture capitalists, and, in 2013, he was recognized by Forbes as one of the top 10 healthcare investors. He has >25 years of experience working with entrepreneurs to found and build successful therapeutics-focused companies. Dr Topper holds a BS from the University of Michigan. He received an MD and PhD (in biophysics) from Stanford University School of Medicine. He completed postgraduate training in internal medicine and cardiovascular disease at the Brigham and Women's Hospital in Boston and is board certified in both disciplines.
P297 Lung-function profile before and after the first moderate to severe exacerbation during the wisdom study
Authors: E Wouters, H Magnussen, R Rodriguez-Roisin, K Tetzlaff, S Bell, PM A Calverley
Journal: Thorax (2016)

<h3>Rationale</h3> The WISDOM study (NCT00975195) showed no increased risk of exacerbation when inhaled corticosteroid (ICS) was withdrawn stepwise in patients with severe COPD on LAMA+LABA maintenance therapy versus continued LAMA+LABA+ICS.<sup>1</sup> Daily home spirometry measured the time course of lung-function changes throughout the study. The aim of this <i>post hoc</i> analysis was to address the lung-function profile leading up to, during and following the first moderate-to-severe exacerbation. <h3>Methods</h3> WISDOM was a multinational, randomised, double-blind study.<sup>1</sup> Patients with severe to very severe COPD entered a 6-week run-in with LAMA+LABA+ICS (tiotropium 18 µg once daily; salmeterol 50 µg twice daily; fluticasone propionate 500 µg twice daily), and were randomised to continue LAMA+LABA+ICS or salmeterol/tiotropium for 52 weeks while discontinuing ICS in a stepwise manner over 12 weeks. On-treatment daily forced expiratory volume in 1 second (FEV<sub>1</sub>) change from baseline was calculated before and after the first moderate-to-severe exacerbation. In this <i>post hoc</i> analysis, we included patients who experienced a moderate-to-severe exacerbation after the ICS-withdrawal visit, did not have an exacerbation in the 8 weeks before or after the exacerbation, and had daily home-measured FEV<sub>1</sub> data available for every week analysed. <h3>Results</h3> Of 2488 patients, 262 experienced a moderate-to-severe exacerbation after the ICS-withdrawal visit and had lung-function data for every week. For all patients combined (ICS and ICS withdrawal), change in FEV<sub>1</sub> remained relatively stable 56–14 days before the first moderate-to-severe exacerbation (mean FEV<sub>1</sub> change from baseline values: −0.04 to −0.07 L) (Figure). There was a decline in lung function starting 2–3 weeks before exacerbation (FEV<sub>1</sub> change value of −0.12 L from baseline), followed by a moderate improvement over ∼14 days. Post-exacerbation lung function did not reach pre-exacerbation levels. <h3>Conclusions</h3> Lung function was relatively stable in both treatment groups. Home spirometry measurements showed a marked decline in FEV<sub>1</sub> prior to moderate-to-severe exacerbation with improvements seen post-exacerbation, although not to pre-exacerbation levels. These findings support the usefulness of home spirometry to predict exacerbations and to indicate subsequent worsening of lung function resulting from a previous COPD exacerbation. <h3>Funding</h3> Boehringer Ingelheim. Please refer to page A273 for declarations of interest in relation to abstract P297. <h3>Reference</h3> Magnussen H, <i>et al</i>. <i>N Engl J Med</i> 2014;<b>371</b>:1285–1294.
OC-064 Risk Factors for Colorectal Neoplasia in Ulcerative Colitis: Results from the Largest and Longest-Running Colonoscopic Surveillance Program
Authors: CHR Choi, I Al Bakir, NSJ Ding, M Moorghen, J Warusavitarne, S Thomas-Gibson, B Saunders, M Rutter, T Graham, A Hart
Journal: Gut (2016)

<h3>Introduction</h3> Whilst patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC), its absolute risk remains very low. As most CRCs develop from pre-existing dysplasia, identifying those patients at high risk of developing dysplasia is important. The aim of this study was to identify risk factors associated with development of colorectal neoplasia (CRN) in patients with UC. <h3>Methods</h3> Patients with extensive UC who were under surveillance from 2003 to 2012 were identified and followed up to July 2013. Each surveillance episode was scored for endoscopic and histological severity of inflammation based on the segment worst affected by colitis: (0, normal/quiescent; 1, mild; 2, moderate; 3, severe active). Potential predictors (n = 18) were correlated against colorectal neoplasia (CRN) outcome, which was defined as non-polypoid low-grade dysplasia, high-grade dysplasia or CRC. To take into account the variables that may change over time, we employed Cox-regression analysis with time-dependent covariates. <h3>Results</h3> A total of 987 UC patients underwent 6,985 colonoscopies (median, 6; interquartile range (IQR), 4–9 per patient) over 12,305 patient-years (median follow-up, 11; IQR, 7–17) since starting their surveillance. Of these, 97 (9.8%) developed CRN (41 cancers). After multivariate analysis, following variables remained as significant contributory factor for the CRN outcome: increased <i>average</i> histological inflammation score (average-<i>HIS</i>; <b>average score of all surveillance colonoscopies for each patient</b>), endoscopic signs of disease chronicity (i.e. tubular, featureless or shortened colon), colonic stricture and primary sclerosing cholangitis (Table 1). Furthermore, while <i>average-HIS </i>was the most influential predictor, <i>HIS</i> of the immediately preceding colonoscopy showed comparable predictive value (Table 1). Post-inflammatory polyps and scarring were not significant at multivariate level. <h3>Conclusion</h3> This is the largest detailed cohort study to date looking at individual risk factors for CRC in UC. Patients with PSC, pertinent macroscopic features (tubular, featureless, shortened colon or stricture) or persistent microscopic inflammation require intensive colonoscopic surveillance. In addition, the histological assessment of inflammation severity at the time of colonoscopy may be used to predict future CRN risk. <h3>Disclosure of Interest</h3> None Declared
Polymorphisms of the Transforming Growth Factor Beta 1 (TGFB1) Gene Define a Subgroup of Patients with Late Onset of Disease and Poor Outcome in Multiple Myeloma.
Authors: Kai Neben, Joannis Mytilineos, Christiane Heiss, Anthony D. Ho, Axel Benner, Gerhard Opelz, Hartmut Goldschmidt
Journal: Blood (2007)
Analysis of the Expression of an Endogenous Tumor Suppressor Gene, PHLPP, and Elevation of PHLPP as an Ideal Target for MRD Monitoring in Leukemia.
Authors: Takaaki Ono, Satoki Nakamura, Yuya Sugimoto, Miki Kobayashi, Naohi Sahara, Kaori Shinjo, Kazuyuki Shigeno, Shinya Fujisawa, Kazunori Ohnishi
Journal: Blood (2006)
Use of a Disease-Specific Comorbidity Index To Describe Elderly Patients with Acute Myelogenous Leukemia (AML) and High Risk Myelodysplasia (MDS) Enrolled in a Phase II Study of CLORETAZINE™ (VNP40101M).
Authors: Francis Giles, David Rizzieri, Judith Karp, Norbert Vey, Khuda Khan, Ghulam Mufti, Diana Hudak, Verena Karsten, Susan O’Brien
Journal: Blood (2005)
PTH-121 Development and Validation of A Training Module on The Use of Acetic Acid Chromoendoscopy (AAC) to Detect Barrett’s Neoplasia: Abstract PTH-121 Table 1
Authors: F Chedgy, K Kandiah, G Longcroft-Wheaton, P Bhandari
Journal: Gut (2016)

<h3>Introduction</h3> Acetic acid chromoendoscopy (AAC) is increasingly used by both expert and non-expert endoscopists for detection of Barrett’s neoplasia. However, there is no validated training strategy to achieve competence. The aim of this study was to identify the need for training, develop a validated training tool in the use of AAC and evaluate its impact on neoplasia detection, degree of confidence of the endoscopists &amp; attitude towards switching to AAC from conventional Barrett’s surveillance strategy. <h3>Methods</h3> A validated assessment tool of 40 images and 20 videos was developed. 13 endoscopists experienced in Barrett’s endoscopy and no formal training in AAC (7 consultants, 6 nurse endoscopists) underwent training. Participants underwent: 1. baseline assessment→online-training→2.assessment→ interactive seminar with live cases→3.assessment. <h3>Results</h3> Experienced endoscopists lack lesion recognition skills with AAC, Consultants perform no better than nurse-endoscopists. There were significant increases in accuracy, sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) following the online training module (Table 1) to a level that meets ASGE PIVI requirements. There was additional gain from the interactive workshop with live &amp; inter-observer agreement improved. The training intervention led to an improvement in the endoscopist’s confidence in AAC, with the mean pre-training confidence level rising from 2.5 (5 point scale) to 3.9 post-training (p &lt; 0.001). The training module improved the willingness of the endoscopists in changing practice from Seattle protocol to AAC-targeted biopsy with mean pre-training confidence score of 2.6 (5 point scale) rising to 3.8 post-training(p &lt; 0.001). <h3>Conclusion</h3> Our data demonstrates the need for training as baseline performance, even by experts, was poor We were successful in developing a validated online training and testing tool for AAC Our training tool improved performance of all endoscopists to a clinically significant (PIVI standard) level &amp; improved their confidence &amp; willingness in the use of AAC. <h3>Disclosure of Interest</h3> None Declared
ARTemis: Randomized trial with neoadjuvant chemotherapy for patients with early breast cancer.
Authors: Helena Margaret Earl, C Blenkinsop, L Grybowicz, A-L Vallier, David A. Cameron, John M.S. Bartlett, Nicholas Murray, Carlos Caldas, J Thomas, Janet A Dunn, Helen B Higgins, Louise Hiller, Larry Hayward
Journal: Journal of Clinical Oncology (2012)

TPS1144 Background: Bevacizumab is a new humanised monoclonal antibody which targets vascular endothelial growth factor (VEGF) and thereby the neoangiogenic process in cancer. Bevacizumab has shown promising anti-tumour effect when given concurrently with taxane-based chemotherapy in breast cancer. However two neoadjuvant breast cancer trials have produced conflicting results. The NSABP-B40 study showed significant benefit for bevacizumab only in the ER+ve patients (pathological complete response (pCR) in ER+ve population 15.2% vs 23.3%, p=0.008). Whereas the GEPARQUINTO trial reported significant benefit only in the triple negative patients (pCR 27.8% vs 36.4% p=0.021). Methods: ARTemis is a phase III randomised trial to determine whether the addition to neo-adjuvant chemotherapy of bevacizumab is more effective than standard chemotherapy alone in patients with HER2-negative early breast cancer. A total of 400 patients will be randomised into each of the two treatment arms which will allow an absolute difference in the pCR rates in excess of 10% to be detected at the 5% (2-sided) level of significance with an 85% power. Primary outcome is pathological complete response rates after neo-adjuvant chemotherapy, i.e. no residual invasive carcinoma in the breast, and no evidence of metastatic disease within the lymph nodes. Secondary outcomes are disease free survival, overall survival, complete pathological response rates in breast alone, radiological response after 3 and 6 cycles of chemotherapy and rate of breast conservation and toxicities. Results: Recruitment into ARTemis began in April 2009 and as of January 2012 had recruited 469 (59%). ARTemis is due to complete recruitment by Dec 2012 and the first planned interim analysis of the primary outcome will be Dec 2013. Conclusion: The IDSMC reviewed the trial in June 2011 and recommended continuation of recruitment to this important trial given there were no safety concerns, and results from the other neoadjuvant studies (NSABP-B40 and GEPARQUINTO) are conflicting.
Performance of a New Global Chromogenic Assay for Protein C Pathway (HemosIL ThromboPath) in the Diagnosis of Lupus Anticoagulant and Antiphospholipid Antibodies.
Authors: Pierre A. Toulon, Isabelle Martin-Toutain, Jean-Charles Piette, Marie-Claude Diemert, Annick Ankri
Journal: Blood (2008)
Absence of Graft Failure and Excellent Long Term Survival Following Fludarabine-Based Reduced Intensity Hematopoietic Stem Cell Transplantation In Heavily Transfused Patients with ATG-Refractory Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes
Authors: Jeremy Pantin, Xin Tian, Nancy Geller, Catalina Ramos, Lisa Cook, Sophia Grasmeder, Philip Scheinberg, Neal S. Young, Sumithira Vasu, Theresa Donohue, Richard Childs
Journal: Blood (2010)