tbuckley/cabot-search huggingface dataset:
PWE-159 Diabetes and Pancreatic Cancer – Cause or Association?
Authors: L Chen, M Kumar
Journal: Gut (2016)

<h3>Introduction</h3> Diabetes is an established risk factor for pancreatic cancer.<sup>1</sup> However, there is still limited evidence around predictors of pancreatic cancer diagnosis and severity in patients with pre-existing diabetes. In this retrospective observational study, we assess the relationship between pre-existing diabetes and pancreatic cancer in a UK patient cohort. In particular, we investigate the association of pre-diagnosis blood glucose levels with onset and severity of pancreatic cancer to determine whether there is a role for screening in diabetic patients. <h3>Methods</h3> Between 2012 and 2014, a total of 188 patients were diagnosed with pancreatic cancer at our regional oncology centre. Data was available for 116 of these patients. Detailed information on pre-diagnosis diabetic status, plasma glucose levels and cancer severity were retrieved systematically from their clinical notes and cancer services database, using standardised forms and procedures. Multivariate logistic regression analysis was used to investigate the association of blood glucose levels 5 years pre-diagnosis with age of cancer diagnosis and TNM staging of the cancer. <h3>Results</h3> Overall, the mean age of diagnosis was 70.8 years and 30% of these patients had pre-existing diabetes, compared to the UK national prevalence of 16.3% (men) and 9.4% (women) for a similar age range (65–74 years).<sup>2</sup> Among those who had died by the time of analysis (n = 37), the age at diagnosis of cancer was 2.4 years younger in patients with pre-existing diabetes than those without. Mean highest blood glucose level 5 years before diagnosis (n = 93) was 7.17 mmol/l in non-diabetics and 15.14 mmol/l in patients with diabetes. Each 1 unit increase of log-transformed blood glucose, regardless of diabetes status, was associated with a 2 year earlier age of diagnosis (p = 0.32) and 4 fold increase of having TNM stage T4/N1/M1 or greater (p = 0.22). <h3>Conclusion</h3> Our study suggests that pancreatic cancer patients had a much higher prevalence of pre-existing diabetes compared with the general population. Raised blood glucose levels appeared to be associated with earlier age of onset, worse staging and prognosis of pancreatic cancer. This study highlights the need for further UK studies to investigate the relationship between high pre-diagnosis blood glucose levels and pancreatic cancer in order to further examine the role of screening in diabetic patients. <h3>References</h3> 1 Muniraj T, Chari ST. Diabetes and pancreatic cancer. <i>Minerva Gastroenterol Dietol</i>. 2012 December;<b>58</b>(4):331–345. 2 Health Survey for England 2011. HSE 2011: Vol 1, Chapter 4: Diabetes and Hyperglycaemia. <h3>Disclosure of Interest</h3> None Declared
AB0700 Baseline Clinical Characteristics of The Leeds Sparro Early Psoriatic Arthritis Cohort: High Disease and Radiographic Involvement Are Seen Early Even in The Presence of Preserved Quality of Life: Table 1.
Authors: M. Merashli, G. De Marco, A.L. Tan, P. Emery, D. Mcgonagle, P. Helliwell, H. Marzo-Ortega
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Data are mounting on the need to treat PsA early to improve long term outcome and prevent disability. There are few cohorts of early untreated PsA reported in the literature with variable characteristics and outcomes which may reflect different geographical and health economic backgrounds. <h3>Objectives</h3> To describe the baseline clinical characteristics of the early PsA cohort recently initiated as part of the Leeds SpARRO (Spondyloarthropathy Register for Research and Observation) study to assess how change in practice implemented through dedicated early synovitis and SpA clinics may affect outcome in SpA. <h3>Methods</h3> Observational study describing baseline clinical characteristics of the first 55 patients recruited to the Leeds SpARRO register with a new diagnosis of PsA. Data are presented as descriptive statistics including demographics, clinical disease activity measures, treatment and patient reported outcomes. <h3>Results</h3> Subjects recruited fulfilled CASPAR criteria [mean disease duration from symptom onset is 1.5±0.6 years]; F:M ratio 1.4; 66% white British; mean BMI 29±6 kg/m<sup>2</sup> and were DMARD naïve (90%) at presentation. The majority were negative for both RF and CCP antibodies (96% [n=53]; with an asymmetrical (67%), polyarticular joint phenotype (73%). Axial involvement was seen in 29% (n=16). As expected, the majority of the cohort was negative for HLA-B27 (76%, n=42). Prevalence of current skin psoriasis was high (91%) although extent and severity were mild (PASI median (IQR) 4 (0–27). Nail involvement was recorded in 50% (mNAPSI mean± SD 8±11). No extra-articular manifestations were seen apart from 1 case with Crohn9s disease. Quality of life scores for skin and joints showed mild impairment [DLQI median (IQR) 4 (1–9)] and PsAQoL [median (IQR) 7.5 (3–12)] however, the PASDAS was consistent with high disease activity mean ±SD (5.6±1.2). Furthermore, baseline radiographic assessment (n=44) showed established change in 25% (n=11) [juxta-articular new bone formation (n=7) and erosions (n=4; all in MTP joints)] of subjects whilst 50% of the total population were smokers (22% n=12 current; 27% n=15 previous). HAQ score (median [IQR] was 0.75 [0.25–1.4]). <h3>Conclusions</h3> Our cohort of early, untreated PsA shows relatively preserved quality of life at baseline highlighting the successful and timely identification of these patients through early arthritis clinics. Still, composite measures of disease activity and radiographic assessment confirm highly active disease and established damage in 25% of cases, emphasizing the need for prompt intervention to achieve immediate disease control and prevent disability and development of co-morbidities in this disease. <h3>Disclosure of Interest</h3> None declared
Rituximab Resistant Follicular Lymphoma: Predictors of Rituximab Resistance, Incidence of Transformation and Prognosis
Authors: Lee Mozessohn, Matthew Cheung, Michael Crump, Rena Buckstein, Neil L Berinstein, Kevin R. Imrie, John Kuruvilla, Eugenia Piliotis, Vishal Kukreti
Journal: Blood (2011)
OC-069 Randomised Controlled Trial – Transcutaneous Auricular Electrical Vagal Nerve Stimulation Prevents the Development of Acid Induced Esophageal Hypersensitivity
Authors: G Amarasinghe, Q Aziz, AD Farmer
Journal: Gut (2016)

<h3>Introduction</h3> We have previously demonstrated that physiologically increasing vagal tone, with deep breathing, prevents the development of acid induced oesophageal pain hypersensitivity.<sup>1</sup> We aimed to determine whether electrical manipulation of parasympathetic tone influences the development of hypersensitivity in a validated model of acid induced oesophageal pain. <h3>Methods</h3> Prior to, and following, a 30 minute distal oesophageal infusion of 0.15 M hydrochloric acid, pain thresholds to electrical stimulation were determined in the proximal non-acid exposed oesophagus in 15 healthy subjects (11 male, mean age 30 years, range 21–42). Validated sympathetic (cardiac sympathetic index) and parasympathetic (cardiac vagal tone) parameters were measured at baseline and continuously thereafter. Subjects were randomised in a blinded crossover design to receive either external auricular electrical vagal nerve stimulation (VNS), or sham stimulation, during acid infusion. <h3>Results</h3> VNS increased cardiac vagal tone (31.6% ± 58.7 vs. -9.6 ± 20.6, <i>p</i> = 0.02) in comparison to sham stimulation. Mixed effects linear regression, controlling for age and gender, demonstrated that VNS prevented the development of acid-induced oesophageal hypersensitivity in comparison to sham stimulation (coefficient 15.4 mA /unit time (95% confidence interval 8.8 to 22.2), p = 0.001). Figure 1 demonstrates the percentage change in pain thresholds following a 30 distal oesophageal acid infusion. <h3>Conclusion</h3> The development of oesophageal hyperalgesia is prevented by electrically stimulating the vagus nerve by increasing parasympathetic tone. This study provides further evidence of the anti-nociceptive role of the parasympathetic nervous system within the oesophagus. Further work is warranted in patients groups such as those with recalcitrant non-erosive reflux disease. <h3>Reference</h3> 1 Botha C, <i>et al</i> . <i>Gut</i> 2014. <h3>Disclosure of Interest</h3> None Declared
Clinical Significance of Myelosuppression Associated with the Use of Dasatinib and Nilotinib As Initial Therapy in Chronic Phase (CP) of Chronic Myeloid Leukemia (CML)
Authors: Theresa Liu-Dumlao, Hagop M. Kantarjian, Alfonso Quintas-Cardama, Elias Jabbour, Jan A. Burger, Yesid Alvarado, Elizabeth M Burton, Long Xuan Trinh, Farhad Ravandi, Alessandra Ferrajoli, Susan O'Brien, Jorge E. Cortes
Journal: Blood (2011)
Interaction between Polymorphisms MTHFR C677T and MTRR A66G and Vitamin Levels in Pregnant Women.
Authors: Elvira M. Guerra-Shinohara, Patricia R. Barbosa, Luiz F. Sampaio-Neto, Rosario D. Hirata, Mario H. Hirata, Robert H. Allen, Sally P. Stabler
Journal: Blood (2004)
MTR-12SUV39H1 INHIBITOR AND EPIGENETIC MODIFIER DRUG CHAETOCIN SENSITIZES GBM CELLS TO TRAIL-INDUCED APOPTOSIS
Authors: Ezgi Özyerli, Zeynep Kahya, Udo Oppermann, Tuğba Bağcı Önder
Journal: Neuro-Oncology (2015)

Glioblastoma Multiforme (GBM) is the most common and aggressive brain tumor, which lacks efficient therapy. TRAIL is an antitumor agent that triggers apoptosis selectively on tumor cells, thus can be utilized as therapeutic approach for GBM. However, most GBM cells confer TRAIL resistance and how this resistance is regulated at a molecular level is not completely clear. Epigenetic deregulation has been increasingly recognized as a hallmark of cancer. In this study, we conducted a drug screen against selected chromatin modifiers in U87MG GBM cells and identified Chaetocin as potential apoptosis regulators whose role in cancers is not well-known and whose relation to TRAIL is novel. Chaetocin is a fungal mycotoxin that inhibits Suv39H1, a histone methyltransferase (HMT) that catalyzes H3K9 methylation. In this study, we investigated how Chaetocin affects the response of GBM cells to apoptotic stimuli by TRAIL. To this end, GBM cell line U87MG is treated with varying dose of Chaetocin and cells' viability and apoptosis responses to varying doses of TRAIL are analyzed. Chaetocin decreased viability down to 11% of control in U87MG cells upon TRAIL treatment, without inducing cellular toxicity and apoptosis by itself. Chaetocin is shown to upregulate the expression of proapoptotic genes while downregulating antiapoptotic gene expression. In addition, elevated Caspase3/7 activity is detected in U87MG upon Chaetocin treatment. We infer from these findings that Chaetocin plays critical and specific role in TRAIL-induced apoptotic pathway. Our future work is directed towards examining the epigenetic changes in apoptosis-associated genes upon Chaetocin treatment and understanding the functional role of SUV39H1 induced H3K9 Methylation in GBM cell apoptosis. These findings support our motivation that identifying epigenetic modifier drugs as a TRAIL sensitizer may be a promising therapeutic approach for GBM treatment.
Pediatric acute liver failure of undetermined cause: A research workshop
Authors: Estella M. Alonso, Simon P. Horslen, Edward M. Behrens, Edward Doo
Journal: Hepatology (2016)

Pediatric acute liver failure (PALF) is a potentially devastating condition that occurs in previously healthy children of all ages and frequently leads to a rapid clinical deterioration. An identified cause for liver injury is lacking in approximately 30% of cases. Children with undetermined diagnosis have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. A single-day workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together clinicians and basic scientists to integrate aligned research findings and develop a foundation for new mechanistic studies and future treatment trials. The clinical phenotype of indeterminate PALF shares important similarities to the hyperinflammatory state characteristic of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). A failure of cytotoxic T cells to limit or contract inflammatory responses may propagate injury and lead to a local and systemic milieu that does not support normal hepatic regeneration. Evidence was presented that bone marrow (BM)-derived Sinusoidal endothelial cell PROgenitor Cells (sprocs) play a vital role in hepatic regeneration. Overwhelming systemic inflammatory responses may suppress mobilization of BM sprocs and dampen hepatic recovery.Experience gained through treatment trials of HLH and MAS in childhood may inform study design for therapy of PALF. Successful approaches to limiting neuroinflammation through reduction of systemic inflammation and standardized neuroprotection protocols that limit glial injury could significantly improve intact survival. Finally, given that PALF is a rare disease, investigative efforts must include broad multicenter collaboration and careful stewardship of biorepository specimens. (Hepatology 2017;65:1026-1037).
The Functional Distance Between Mismatched HLA-DPB1 Increases Risks of Relapse and Mortality after Unrelated Donor Hematopoietic Cell Transplantation for AML, ALL and MDS: A Refinement of the T Cell Epitope Group Algorithm for Permissive Mismatches
Authors: Dietrich W. Beelen, Pietro Crivello, Andreas Heinold, Sabine Riebschläger, Falko M. Heinemann, Vera Rebmann, Monika Lindemann, Hellmut Ottinger, Peter Horn, Katharina Fleischhauer
Journal: Blood (2015)
Biological and Clinical Features of Patients with Acute Myeloid Leukemia Bearing Trisomy 21
Authors: Paolo Strati, Hagop M. Kantarjian, Jorge E. Cortes, Farhad Ravandi, Naveen Pemmaraju, Guillermo Garcia-Manero, Tapan M. Kadia, Elias J. Jabbour, Aziz Nazha, Gautam Borthakur, Stefan Faderl, Alfonso Quintás-Cardama, Naval G. Daver
Journal: Blood (2012)
Long Noncoding RNAs in Cardiovascular Pathology, Diagnosis, and Therapy
Authors: Christian Bär, Shambhabi Chatterjee, Thomas Thum
Journal: Circulation (2016)

Vast parts of mammalian genomes encode for transcripts that are not further translated into proteins. The purpose of the majority of such noncoding ribonucleic acids (RNAs) remained paradoxical for a long time. However, a growing body of evidence demonstrates that long noncoding RNAs are dynamically expressed in different cell types, diseases, or developmental stages to execute a wide variety of regulatory roles at virtually every step of gene expression and translation. Indeed, long noncoding RNAs influence gene expression via epigenetic modulations, through regulating alternative splicing, or by acting as molecular sponges. The abundance of long noncoding RNAs in the cardiovascular system indicates that they may be part of a complex regulatory network governing physiology and pathology of the heart. In this review, we discuss the multifaceted functions of long noncoding RNAs and highlight the current literature with an emphasis on cardiac development and disease. Furthermore, as the enormous spectrum of long noncoding RNAs potentially opens up new avenues for diagnosis and prevention of heart failure, we ultimately evaluate the futuristic prospects of long noncoding RNAs as biomarkers, and therapeutic targets for the treatment of cardiovascular disorders, as well.
SAT0340 Distinct Distribution Patterns of Large Vessel Vasculitis Assessed with 18f-FDG PET/CT: A Cluster and Principal Component Analysis Study
Authors: A. Soriano, G. Pazzola, L. Boiardi, F. Muratore, P. Macchioni, R. Aldigeri, M. Casali, A. Versari, C. Salvarani
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> The interpretation of data from 18F-FDG PET/CT studies on large vessel vasculitis (LVV) is difficult due to the scarcity of studies and to the heterogeneity of LVV populations examined. In the absence of gold standard parameters for the assessment of LVV arterial inflammation, there is a great need to develop analytical methodologies useful to properly exploit the information derived from such studies. Principal component analysis (PCA) and cluster analysis (CA) have not yet been applied to explore the LVV distribution patterns, assessed by 18F-FDG PET/CT. <h3>Objectives</h3> The aim of our study was to investigate whether PCA and CA are useful methods in identifying distinct distribution patterns of LVV, according to the specific diagnostic entity examined (giant cell arteritis, GCA; Takayasu9s arteritis, TAK). <h3>Methods</h3> A total of 130 18F-FDG PET/CT studies have been retrospectively examined by a nuclear physician blinded to clinical data. Maximum standardized uptake values (SUVmax) in 14 vascular districts including aortic segments (ascending aorta, thoracic aorta, aortic arch, discending thoracic aorta and abdominal aorta) and the main tributaries (carotid, subclavian, axillary, iliac and femoral arteries) have been measured and transformed into Z-scores. Identification of distribution patterns of vascular involvement has been performed using PCA and agglomerative hierarchical CA (SPSS Statistics, version 22nd). <h3>Results</h3> Three groups of vascular districts with similar trends in terms of standardized SUVmax have been identified: epiaortic arteries; aortic arch and ascending aorta; descending and abdominal aorta, with iliac and femoral arteries. A component including the entire aortic district was identified in TAK group, but not in GCA group. <h3>Conclusions</h3> PCA and CA approach revealed a subtle skewing in terms of distribution patterns of arterial involvement between TAK and GCA, assessed by 18F-FDG PET/CT SUVmax values. The influence of atherosclerosis and immunosenescence on the different trends in the aorta districts of TAK and GCA needs to be further elucidated. <h3>References</h3> Grayson PC, et al. Distribution of arterial lesions in Takayasu9s arteritis and giant cell arteritis. Ann Rheum Dis 2012;71:1329–1334. Arnaud L, et al. Cluster analysis of arterial involvement in Takayasu arteritis reveals symmetric extension of the lesions in paired arterial beds. Arthritis Rheum 2011;63:1136–40. <h3>Disclosure of Interest</h3> None declared
Nickel pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via both Bcr/Abl-dependent and Bcr/Abl-independent mechanisms
Authors: Xiaoying Lan, Chong Zhao, Xin Chen, Peiquan Zhang, Dan Zang, Jinjie Wu, Jinghong Chen, Huidan Long, Li Yang, Hongbiao Huang, Bing Z. Carter, Xuejun Wang, Xianping Shi, Jinbao Liu
Journal: Journal of Hematology & Oncology (2016)

Acquired imatinib (IM) resistance is frequently characterized by Bcr-Abl mutations that affect IM binding and kinase inhibition in patients with chronic myelogenous leukemia (CML). Bcr-Abl-T315I mutation is the predominant mechanism of the acquired resistance to IM. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that nickel pyrithione (NiPT) potently inhibits the ubiquitin proteasome system via targeting the 19S proteasome-associated deubiquitinases (UCHL5 and USP14), without effecting on the 20S proteasome. In this present study, we investigated the effect of NiPT, a novel proteasomal deubiquitinase inhibitor, on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl. Cell viability was examined by MTS assay and trypan blue exclusion staining assay in KBM5, KBM5R, K562, BaF3-p210-WT, BaF3-p210-T315I cells, and CML patients' bone marrow samples treated with NiPT. Cell apoptosis in CML cells was detected with Annexin V-FITC/PI and rhodamine-123 staining followed by fluorescence microscopy and flow cytometry and with western blot analyses for apoptosis-associated proteins. Expression levels of Bcr-Abl in CML cells were analyzed by using western blotting and real-time PCR. The 20S proteasome peptidase activity was measured using specific fluorogenic substrate. Active-site-directed labeling of proteasomal DUBs, as well as the phosphorylation of USP14 was used for evaluating the inhibition of the DUBs activity by NiPT. Mouse xenograft models of KBM5 and KBM5R cells were analyzed, and Bcr-Abl-related proteins and protein biomarkers related to proliferation, differentiation, and adhesion in tumor tissues were detected by western blots and/or immunohistological analyses. NiPT induced apoptosis in CML cells and inhibited the growth of IM-resistant Bcr-Abl-T315I xenografts in nude mice. Mechanistically, NiPT induced decreases in Bcr-Abl proteins, which were associated with downregulation of Bcr-Abl transcription and with the cleavage of Bcr-Abl protein by activated caspases. NiPT-induced ubiquitin proteasome system inhibition induced caspase activation in both IM-resistant and IM-sensitive CML cells, and the caspase activation was required for NiPT-induced Bcr-Abl downregulation and apoptotic cell death. These findings support that NiPT can overcome IM resistance through both Bcr-Abl-dependent and Bcr-Abl-independent mechanisms, providing potentially a new option for CML treatment.
AB0884 Diagnostic Value of Procalcitonin for Differentiation between Bacterial Infection and Non Infectious Inflammation in Febrile Children with Systemic Autoimmune Disease
Authors: S. Kumar, S.K. Loganathan
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Systemic autoimmune disease children presents with fever during disease flare and systemic infection. It is very difficult for clinician to decide the diagnosis clinically, acute phase reactants helps in this situation. Hence we decided to determine the diagnostic value of procalcitonin to differentiate bacterial infection and non infectious inflammation. <h3>Objectives</h3> To determine the clinical value of procalcitonin (PCT) in differentiating bacterial infection from disease activity in children with systemic autoimmune disease. <h3>Methods</h3> This was a cross-sectional study of children with systemic autoimmune disease presented with fever recruited over 9 months. Baseline demographic variables were recorded and measurements of PCT, CRP, ESR and blood cultures were done. The disease activity for SLE was determined by SLEDAI score and for JIA by Wallace criteria. During the study period, 24 children with systemic autoimmune disease were recruited and analysed. Children were divided in 2 groups: Fever due to disease flare and due to infections. <h3>Results</h3> Out of 24 children recruited as per inclusion criteria, 16 had SLE (11 in disease flare group and 5 in infection group) and 8 had disease flare of Systemic JIA. 2 children in SLE infection group died. As for infections, serum PCT concentration (cut-off value &gt;1.2 ng/ml) gave a sensitivity of 83% (95% CI 43.6 - 0.97), a specificity of 72% (95% CI 49.1–87.5), a positive predictive value of 50% (95% CI 23.6- 76.3) and a negative predictive value of 93% (95% CI 68.5 - 98.7).To achieve the same sensitivity (as of PCT) of 83%, the cut off value for CRP was 34 mg/dl and ESR was 76 mm/hr. Mean PCT was 92.2 ng/ml in SLE infectious group and 3.50 ng/ml in SLE flare group which was statistically significant (p=0.009). But mean CRP was 98 mg/dl in SLE infectious group and 52 mg/dl in SLE flare group which was not statistically significant (p=0.25). Similarly mean ESR level (38 mm/hr) in SLE infectious group and in SLE flare group (66 mm/hr) was not statistically significant (p=0.35). <h3>Conclusions</h3> Our results suggested that the procalcitonin level was the most discriminatory parameter, followed by CRP in children with SLE presenting with fever between disease flare and infection. Procalcitonin levels&gt;1.2 ng/ml in febrile SLE patients should point to bacterial infection, whereas procalcitonin levels less than &lt;1.2 ng/ml might indicate non-infectious inflammation that could reduce unnecessary antibiotic use. <h3>Disclosure of Interest</h3> None declared