tbuckley/cabot-search huggingface dataset:
Abstract 5076: Dissection of RAS downstream pathways in melanomagenesis
Authors: Prasun J. Mishra, Linan Ha, Jennifer Rieker, Elena Sviderskaya, Dorothy Bennett, Michael D. Oberst, Kathleen Kelly, Glenn Merlino
Journal: Cancer Research (2010)

Abstract Cutaneous malignant melanoma is considered one of the most deadly human cancers, based upon both its penchant for metastatic spread and its typical resistance to currently available therapy. Long known to harbor oncogenic NRAS mutations, melanomas were more recently reported to be frequent bearers of activating mutations in BRAF, one of the effectors situated downstream of wildtype NRAS. RAS gene products (HRas, KRas and NRas) are 21kd G-proteins that serve as molecular switches converting cell-surface kinase activation events to nuclear events, thus influencing cell behavior. The major downstream effectors of Ras are the Rafs (ARaf, BRaf and CRaf), phosphatidylinositol 3-kinase (PI3K) and the Ral guanine exchange factors (RalGEF). NRAS and BRAF mutations are rarely found in the same melanoma, suggesting that they may possess important overlapping oncogenic activities. Here we compare and contrast the oncogenic roles of the three major NRas downstream effectors, Raf, PI3K and RalGEF, using genetically engineered Arf-deficient immortalized mouse melanocytes as a model system. Activation of each of the three major downstream pathways of NRas has overt phenotypic effects on immortalized mouse melanocytes, many distinct. Our data indicate a prominent role for BRaf and PI3K in melanocyte senescence and invasiveness, respectively. More surprisingly, we found that constitutively activated RalGEF stimulated melanocyte invasiveness and anchorage-independent growth almost as impressively as NRasQ61K. The suppressive effects of expression of a dominant negative Ral corroborated the role of the RalGEF-Ral pathway in anchorage-independent growth. Although no single downstream pathway could recapitulate all of the consequences of oncogenic NRas expression, melanocytes expressing constitutively activated mutants of all three NRas downstream factors (RLF-CAAX plus p110α-CAAX plus BRafV600E) achieved soft agar colony forming efficiency that was fully comparable to those expressing NRasQ61K alone. In conclusion, our data suggested a distinct function for all three NRas downstream pathways - Raf, PI3K and Ral in melanocyte senescence, invasiveness and transformation, respectively. Importantly, our finding that constitutive RalGEF activation confers malignant phenotypes in melanocytes, particularly anchorage-independent growth, indicates that this often overlooked pathway should be more carefully evaluated as a possible therapeutic target. 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 5076.
A2.10 SLE associated<i>UBE2L3</i>haplotype modulates plasma cell differentiation via genotypic regulation of NF-κB
Authors: S Vyse, AM Shields, S Boeltz, D Leirer, PA Gordon, TD Spector, PJ Lehner, H Walczak, TJ Vyse, MJ Lewis
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Genome-wide association studies have identified a strong association between a single risk haplotype of the <i>UBE2L3</i> gene and systemic lupus erythematosus (SLE). UBE2L3 is an E2 ubiquitin-conjugating enzyme that critically regulates ubiquitination by the linear ubiquitin chain assembly complex (LUBAC) with consequent effects on NF-kB signalling and inflammatory responses. Herein, we dissect the role of UBE2L3 in regulating NF-kB signalling in human B-cells and monocytes and demonstrate the risk haplotype drives plasmablast and plasma cell expansion in patients with SLE. <h3>Materials and methods</h3> <i>UBE2L3</i> genotype data from GWAS in SLE was imputed using 1000 Genomes reference data. UBE2L3 function and signalling pathways were studied <i>in vitro</i> in HEK293 cells, or <i>ex vivo</i> using B cells and monocytes from healthy individuals or SLE patients (NF-kB translocation by Imagestream, multicolour flow cytometry of B cell subsets) stratified by <i>UBE2L3</i> genotype. Parameters of SLE disease activity were collected and correlated with flow cytometry results. <h3>Results</h3> Data from SLE GWAS, imputed to 1000 Genomes level identified rs140490 as the most strongly associated <i>UBE2L3</i> SNP, located at -270bp of the promoter region (p = 8.6 × 10–14; OR 1.30, 95% CI: 1.21–1.39). Microarray/western blot studies found that the rs140490 risk allele correlated with increased UBE2L3 expression in human B cells and monocytes. Overexpression of UBE2L3 in combination with LUBAC in HEK293-NF-kB reporter cell lines led to marked upregulation of NF-kB activity, which was abolished by a dominant-negative mutant UBE2L3[C86S]. RNAi blockade of UBE2L3 antagonised TNF signalling by inhibiting IκBα processing. UBE2L3 expression was 3–4-fold elevated in peripheral blood plasmablasts and plasma cells (p &lt; 0.0001), with increased UBE2L3 expression in plasma cells from SLE patients compared to controls (p = 0.01). The T/T genotype at rs140490 was associated with a significant expansion in plasmablast and plasma cell populations in SLE patients (both p &lt; 0.001), and showed a trend to correlation with increased SLEDAI scores (p = 0.06). Imagestream analysis demonstrated that rs140490 genotype correlated with both basal NF-kB activation in healthy individuals, as well as the sensitivity of NF-kB to CD40 stimulation in B cells and TNF stimulation in monocytes. <h3>Conclusions</h3> The <i> UBE2L3</i> risk haplotype exerts a critical rate-limiting effect on TNF and CD40 signalling through regulation of LUBAC and NF-kB activation. This is the first demonstration that a complex trait variant at <i>UBE2L3 </i>regulates both basal NF-kB activation and sensitivity of NF-kB to stimulation in <i>ex vivo</i> human cells, resulting in accelerated B cell differentiation in SLE.
Identification and characterization of rapidly dividing U937 clones with differential telomerase activity and gene expression profiles: role of c-Myc/Mad1 and Id/Ets proteins
Authors: X Xiao, SK Phogat, IA Sidorov, J Yang, I Horikawa, D Prieto, J Adelesberger, R Lempicki, JC Barrett, DS Dimitrov
Journal: Leukemia (2002)
Abstract 3160: Open-source RNAi genetic screen platform: discovery of drug targets in cancer cell models.
Authors: Andrei Komarov, Mikhail Makhanov, Elena Komarova, Lilya Novototzkaja, Michael Yeluashvili, Dmitry Suchkov, Kyle Bonneau, Donato Tedesco, Costa G. Frangou, Paul Diehl, Debbie Deng, Karim Hyder, Pavel Komarov, Andrei Gudkov, Alex Chenchik
Journal: Cancer Research (2013)

Abstract We have developed an open-source RNAi genetic screening technology, funded in part by NIH grants and freely available to the scientific community. This platform can be used for functional discovery of drug targets associated with viability and regulation of signaling pathways in cancer cells. Here we present a novel, free public resource for genome-wide RNAi screens: DECIPHER pooled lentiviral shRNA libraries. Results are shown from two RNAi screens with DECIPHER shRNA libraries: one “drop-out” screen to identify genes essential for viability in a panel of leukemic cells, and a second “rescue” screen to identify genes required for FAS induced apoptosis. Both screens found a combination of known and novel signaling pathway and regulatory genes whose functions were confirmed to be required to produce the biological responses. From the viability screens in the panel of leukemia cell lines, subsequent validation using single shRNA-expressing constructs showed that about 80% of the shRNAs identified in each complex library screen did in fact lead to cell death when transduced in cells. Analysis of the identified essential genes for known biological interactions revealed non-random clusters of interacting proteins that provide a useful strategy for prioritization of potential targets. Analysis of the lethal combinations indicates redundant, complementary, and compensatory responses in cancer cells. In the case of the FAS-induced apoptosis, in vitro screening data also enabled us to select targets that protected mice from FAS-induced hepatic failure. These results demonstrate that complex pooled shRNA libraries provide a highly efficient, flexible, and cost-effective alternative to array-based RNAi screening methods for identifying genes regulating biological responses and possible new therapeutic targets. Citation Format: Andrei Komarov, Mikhail Makhanov, Elena Komarova, Lilya Novototzkaja, Michael Yeluashvili, Dmitry Suchkov, Kyle Bonneau, Donato Tedesco, Costa G. Frangou, Paul Diehl, Debbie Deng, Karim Hyder, Pavel Komarov, Andrei Gudkov, Alex Chenchik. Open-source RNAi genetic screen platform: discovery of drug targets in cancer cell models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3160. doi:10.1158/1538-7445.AM2013-3160
Abstract LB-57: Susan G. Komen for the Cure- A global breast cancer movement
Authors: Lee Halarewicz
Journal: Cancer Research (2012)

Abstract Twenty-two Northeast Ohio counties comprise the Northeast Ohio Affiliate for which I volunteer. The Northeast Ohio Affiliate is dedicated to combating breast cancer at every front. Up to 75% of the Affiliate's net income goes toward funding grants to local hospitals and community organizations that provide breast health education and breast cancer screening and treatment programs for medically underserved women. The Affiliate is the only community resource in the Northeast Ohio region positioned to impact the core issues in ways significant enough to improve breast cancer screening rates, which will ultimately lead to a reduction in late stage diagnosis The remaining net income (a minimum of 25%) the Northeast Ohio Affiliate raises supports the national Komen Grants Program, which funds groundbreaking breast cancer research, meritorious awards and educational and scientific programs around the world. The impact of Komen's research investments is evident in every major advance in breast cancer over the past 25 years. Advocate participation in peer review is extended to involvement in many of these ongoing research projects and to other scientific activities through the Advocates in Science program. The Komen Advocates in Science (AIS) program is an inclusive community of dedicated volunteer advocates in scientific breast cancer research. We are brought together and sponsored by Komen to foster excellence in research advocacy and spur greater advocate engagement in research related activities. As an AIS Research Advocate, I participate in a variety of scientific activities to ensure that the unique and valuable perspectives of cancer survivors and others affected by cancer are integrated into scientific dialogue and decisions affecting our progress toward ending breast cancer. Advocates bring a real-world understanding of what most impacts those affected by breast cancer, and they also bring an urgency to find cures and more effective prevention, diagnosis and treatment. Additionally, AIS members engage in ongoing education to enhance our advocacy skills and expand our scientific knowledge. 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 LB-57. doi:1538-7445.AM2012-LB-57
PTH-347 Assessing the safety and feasibility of robotic assisted surgery for rectal and anal cancer: Abstract PTH-347 Table 1
Authors: T Bullen, C Selvasekar, PE Fulford, MS Wilson, O Aziz, AG Renehan, ST O’Dwyer
Journal: Gut (2015)

<h3>Introduction</h3> Management of anorectal cancers has evolved with neo-adjuvant chemoradiotherapy and minimal access surgery. Robotic surgery offers benefits of enhanced 3-D vision and articulated instrumentation that facilitate precise dissection, alleviating some of the challenges in the pelvis. The UK adoption of robotic rectal surgery (RRS) has been slow. This study assesses the feasibility and safety of introducing RRS for anorectal cancers. We analysed short-term outcomes with key pathological markers including stage, circumferential resection margin (CRM) and lymph node status. <h3>Method</h3> Data collected from a prospective database over a three year period was supplemented by case note review. RRS involves a hybrid approach; the abdominal part performed laparoscopically and the pelvic part robotically. <h3>Results</h3> Using the Da Vinci S robot, we performed 38 procedures (23 male: 15 female), median age 64 years (range: 31–82), BMI 26 (17–37) and median ASA 2 (1–4). Indications were 32 rectal cancers (2 recurrent), 2 polyps, 3 anal SCC and 1 peri-anal Pagets’ disease. Of the rectal cancers 3 (9%) received no radiotherapy; 6 (19%) short course and 23 (72%) long course (CRx). Tumours were sited from anal verge to a height of 17.5 cm (median 5.5 cm). As a tertiary referral centre with a referral bias towards locally advanced rectal cancers (24 initial staging T3/4) nine tumours required anterior resection (AR), 20 abdominoperineal excision (APR) (1 included resection of seminal vesicles) and 3 posterior clearances. There was one conversion. Hospital stay ranged 5–25 days (median 8) with no mortality and 4 (13%) complications (National Cancer Institute Common Terminology Criteria for Adverse Events grade 3/4). These include pneumonia, ileus, sepsis with atrial fibrillation (grade 3) and hydronephrosis (grade 4). Four patients developed recurrent disease (1 local, 1 groin, 2 liver) during median follow up of 8 months (range 0–26). Local recurrence occurred 11 months following APR (prior CRx) for a mucinous carcinoma with a CRM of 1mm. Distant metastases were 5, 18 and 23 months post surgery. One patient died of recurrent disease. There was no 30 day mortality. <h3>Conclusion</h3> We performed standard and complex RRS for anorectal cancers, our approach is safe with low morbidity and 0% mortality. Further work is required to assess cost effectiveness, medium and long-term cancer specific and overall outcomes compared to laparoscopic and open techniques. <h3>Disclosure of interest</h3> None Declared.
FRI0084 The presence of magnetic resonance imaging-proven osteitis at entry predicts the development of rapid radiographic progression in patients with early rheumatoid arthritis
Authors: M. Tamai, Y. Nakashima, T. Suzuki, A. Okada, J. Kita, Y. Horai, S.-Y. Kawashiri, N. Iwamoto, K. Ichinose, K. Arima, S. Yamasaki, H. Nakamura, T. Origuchi, M. Uetani, K. Aoyagi, K. Eguchi, A. Kawakami
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Magnetic resonance imaging (MRI) is known as high sensitive imaging modality toward the patients with rheumatoid arthritis (RA). We have reported an importance of MRI-proven symmetrical synovitis, osteitis and bone erosion of wrist and finger joints toward the early diagnosis of RA from the prospective early arthritis cohort at Nagasaki University, Japan. <h3>Objectives</h3> To investigate whether MRI assessment of joint injury predict the development of rapid radiographic progression (RRP) in early RA patients by our cohort. <h3>Methods</h3> Ninety-five RA patients, who fulfilled 2010 RA classification criteria and introduced disease-modifying antirheumatic drugs (DMARDs) including biologics within the first 1 year, were consecutively enrolled in this study. All of the subjects had been examined by gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced MRI and plain radiograph of both wrist and finger joints every 6 months during 2 years. Synovitis, osteitis and bone erosion in MRI were determined by RAMRI scoring (RAMRIS) technique. RRP in the present study was defined as yearly progression of Genant-modified Sharp score &gt;3.0. <h3>Results</h3> The mean disease duration, age, tender joint count (TJC) 28, swollen joint count (SJC) 28, prevalence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA) at entry were 3.7 months, 55.7 years-old, 9.9, 4.9, 54.7% and 57.9%, respectively. The frequency of symmetrical synovitis, osteitis and bone erosion proved by MRI at entry was 82.1%, 46.8% and 32.9%, respectively. Seventeen patients (17.5%) were classified as RRP at 2 years. RF (p=0.017), ACPA (p=0.0013) and MRI-proven osteitis (p=0.040) at entry were defined as the variables to predict the development of RRP at 2 years. <h3>Conclusions</h3> In addition to the diagnostic assessment, the present study has revealed that MRI-proven osteitis at entry is a prognostic marker in patients with early RA. <h3>Disclosure of Interest</h3> None Declared
Cardiovascular safety of the 5-HT3-receptor antagonists readdressed
Authors: D. C. Talbot, A. L. Harris
Journal: Journal of Clinical Oncology (2004)

8209 Background: Of the available 5-HT3-receptor antagonists (RAs), dolasetron, tropisetron and palonosetron include cardiovascular (CV) warnings/precautions in their labelling that should be considered when using these products in patients with existing or possible cardiac impairment. A recent report reviewed CV safety among 5-HT3-RAs and suggested that ECG alteration is a class effect.1 In contrast, other recently published reports demonstrate important differences regarding CV safety. Methods: This review will readdress issues regarding CV safety among 5-HT3-RAs. Results: Clinical trials demonstrate that dolasetron is associated with increases in PR, QRS and QTc intervals and increased heart rate, whereas granisetron and ondansetron lack proarrhythmic activity.2 Recently, a ‘signal’ for ventricular arrhythmia and cardiac arrest was found for dolasetron but not granisetron in the FDA combined SRS/AERS database (adverse events 1966–present).3 Granisetron is not associated with significant CV changes, even at doses as high as 160 μg/kg.4 Ondansetron does not have a CV precaution, but a significant increase in QTc interval has been reported with higher doses.5 Contrary to the idea that all 5-HT3-RAs carry a similar CV risk, evidence in patients and healthy volunteers suggests otherwise.3 However, whether trials have reported asymptomatic or clinically relevant 5-HT3-RA-evoked CV changes may be of little relevance, as the issue of CV safety should be considered in context: elderly patients represent the majority of cancer patients and CV comorbidity is common in this population. Conclusions: QT interval changes have been linked with sudden cardiac death. Thus the CV safety of cancer and supportive therapies, and their additive complications, should be a consideration when choosing therapy. Therefore, it seems prudent to use a 5-HT3-RA that has no warning/precaution concerning CV safety. 1 Navari, Koeller. Ann Pharmacother 2003;37:1276–86 2 Keefe. Oncologist 2002;7:65–72 3 Schnell, Coop. SIOG 2003;37 4 Carmichael, Harris. Anti-Cancer Drugs 2003;14:739–44 5 Boike et al. Am J Health-Syst Pharm 1997;54:1172–6 # Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Kudos; Xenova Xenova Xenova Oxford Biomedica Attenuon
SP0171 How to Optimize Health Professional Input in your Practice: What Can a Nurse Contribute
Authors: J. Ammerlaan
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> People with a rheumatic disease must find ways to effectively manage their physical, emotional, employment an social impacts on their lives, as well as manage their medications and hospital appointment (1). Besides rheumatologists, other health professionals such as occupational therapists, physiotherapists and rheumatology nurses are involved to support patients in this process. Rheumatology nurses provide health care to individuals, families and communities and fulfill advanced and extended roles. These include self-management support, patient education and counseling, intra-articular injections, recommendations for and the prescription of drug treatment, referral to other health professionals, hospital administration of patients, manning telephone advice or e-consultation and monitoring disease-modifying and biological treatments (2). The role of rheumatology nurses differs greatly between countries, due to the educational level, certification and experience as well as to national regulations, contexts and funding issues related to overall healthcare provision (2,3). In several European countries, rheumatology as nursing specialty does not even exist. In other countries, rheumatology nursing has developed into a recognized specialty. In 2011, EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis were developed. These recommendations provide a basis for emphasizing and optimizing rheumatology nursing care, in order to provide a more standardized level of professional rheumatology nursing across Europe (2). <h3>Learning experiences</h3> During this multidisciplinary session the participants will meet: a. the development of rheumatology nursing in the Netherlands throughout the years b. an inside view in the daily practice of a rheumatology nurse c. the contribution a rheumatology nurse in the multidisciplinary team <h3>References</h3> Ryan S, Hassell AB, Lewis M, et al. Impact of a rheumatology expert nurse on the wellbeing of patients attending a drug monitoring clinic. J Adv Nurs 2006;53:277-86 van Eijk-Hustings Y, van Tubergen A, Boström C, et al. EULAR recommendations for the role of the nurse in the management of chornic inflammatory arthritis. Ann Rheum Dis 2012;71:13-19 MacIsaac A, Collichia R, Helm J, et al. Standards of Practice: Professional Nursing Competencies in Rheumatology. American College of Rheumatology http://www.rheumatology.org/practice/clinical/standards/nursestandards.asp <h3>Disclosure of Interest</h3> None Declared