tbuckley/cabot-search huggingface dataset:
Abstract 233: Crosstalk of Her2 signaling and cell cycle control in the response to targeted therapeutics in breast cancer
Authors: Dayana Rivadeneira, Isabelle Mercier, Michael P. Lisanti, Agnieska Witkiewicz, Erik S. Knudsen
Journal: Cancer Research (2011)

Abstract Previous studies have shown that breast cancer is associated with genetic and molecular modifications, such as aberrant amplification of oncogenes and/or inactivation of tumor suppressors. This heterogeneity translates into a wide range of breast cancer subtypes that exhibit different disease behaviors and therapeutic sensitivity. A common oncogenic activation used to classify subtypes of breast cancer is the overexpression of human epidermal growth factor receptor 2 (Her2). These highly aggressive tumors present distinct characteristics in disease progression and therapeutic response. One of the main complications with current therapies is therapeutic bypass and disease recurrence. Therefore, a better understanding of the mechanisms of therapy resistance and the development of alternative downstream interventions is of utmost significance. There are several signaling cascades involved in tumor development that can be activated by the Her2 receptor tyrosine kinases. These signals ultimately converge on the cell cycle machinery, leading to the functional inactivation of RB to promote aberrant cell cycle progression and cell growth. In this context, RB pathway inactivation has been associated with aggressive tumor behavior and poor prognosis in breast cancer. In the current study, we explore the impact of RB inactivation in Her2 overexpressing disease in the response to Her2/EGFR antagonists. Furthermore, we assess the efficacy of reactivating the RB-pathway as a downstream therapeutic alternative in the treatment of Her2 overexpressing tumors and therapy-resistant disease in vitro and in vivo. In vitro studies demonstrate that RB loss can modulate the response to a Her2/EGFR antagonist. Alternatively, results indicate that a novel therapeutic agent that specifically targets cyclin dependent kinase 4 and 6 (CDK4/6) activity dramatically and efficiently inhibits acini/cell growth. Furthermore, CDK4/6 inhibition prevents the formation of multiacinar structures characteristic of Her2 overexpression. Furthermore, a Her2 overexpressing mouse mammary tumor model was utilized to confirm our in vitro findings. These studies indicate that CDK4/6 inhibition was effective in suppressing tumor cell proliferation in vivo. Combined, these findings provide further insight into the crosstalk between Her2 signaling and cell cycle control in the context of therapeutic response, and introduce a novel mode of therapeutic intervention. 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 233. doi:10.1158/1538-7445.AM2011-233
P156 Does analysis of patient-ventilator interaction offer benefits in addition to overnight pulse oximetry in patients with motor neurone disease being followed on non-invasive ventilation?
Authors: B. Chakrabarti, H. Ando, E. Thornton, V. Ford, C. A. Young, R. M. Angus
Journal: Thorax (2010)

<h3>Introduction</h3> Non-invasiveventilation (NIV) is increasingly being offered to Motor Neurone Disease (MND) patients as studies report benefit insurvival and quality of life (QoL). Ventilator technology allows monitoring of patient–ventilator interaction. It is less clear whether such data yield useful additional information over pulse overnight oximetry. In a longitudinal study, MND patients were assessed both physiologically and psychologically prior to NIV initiation and 3monthly until death. <h3>Methods</h3> 35 patients were enrolled; 28 offered NIV; 11 declined and 17 established on treatment. At initiation all had nocturnal hypoventilation by symptoms andoximetry criteria. Nine patients (8 male; median age 60 years) had ≥12 months follow-up on ventilation; none required oxygen with NIV. Patient–ventilator interaction was assessed by analysis of the ‘memory card’ from the ventilator at 4–6 months post initiation (Point A) and at 10–12 months (Point B); QoL assessed by validated questionnaires within 2 weeks of memory card analysis. <h3>Results</h3> Median overnight oxygen saturation in the sample was 93% at point A and 94% at B; only 3 and 2 patients respectively exhibited ‘sub-optimal’ oximetry that is, &gt;30 min below 90% saturation resulting in adjustment of ventilation. Minute Ventilation (MV) fell in the group from Point A to B (mean 6.97–6.34 l/min); a fall in MV (noted in five patients of which 1 exhibited “sub-optimal” oximetry) was associated with a fall in ALS FRS score denoting worsening health status (correlation coefficient 0.73; p=0.026). Ventilator triggering decreased overall in the group from Points A to B (mean 69.95–61.57% proportion of triggered breaths); a decrease in ventilator triggering (noted in six patients of which 1 exhibited “sub-optimal” oximetry) correlated with an increase in ALS AQ domain for emotion denoting worsening emotional functioning (correlation coefficient −0.89; p=0.002) with anon-significant trend noted between fall in triggered breaths and increase in Hospital Anxiety and Depression (HAD) score (correlation coefficient −0.68; p=0.055). <h3>Conclusion</h3> In MND, monitoring of patient–ventilator interaction may serve as a useful adjunct to pulse oximetry and symptom assessment. Further studies are needed to ascertain whether adjustment of ventilation based on this approach allows patients to gain full benefit from NIV.
Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease
Authors: Huiling Wang, Kang Chao, Siew Chien Ng, Alfa Hc Bai, Qiao Yu, Jun Yu, Manying Li, Yi Cui, Minhu Chen, Ji-Fan Hu, Shenghong Zhang
Journal: Genome biology (2016)

The IL23/Th17 pathway is essential for the onset of inflammatory bowel disease (IBD), yet the specific mechanism by which this pathway initiates the disease remains unknown. In this study, we identify the mechanisms that mediate cross-talk between the IL23 pathway and the intestinal barrier in IBD. The downstream targets of the IL23 pathway were identified by RNA array profiling and confirmed by immunohistochemical staining. The role of miRNAs that interact with IL23 was explored in mice with TNBS-induced colitis. Claudin-8 (CLDN8), a multigene family protein that constitutes the backbone of tight junctions, was identified as a novel target of IL23 in IBD. CLDN8 was significantly downregulated in IBD patients with inflamed colonic mucosa, and in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice. Therapeutic treatment of colitis in mice using an IL23 antibody restored CLDN8 abundance, in parallel with recovery from colitis. In addition, we identify miR-223 as a novel mediator of the crosstalk between the IL23 signal pathway and CLDN8 in the development of IBD. MiR-223 was upregulated in IBD, and its activity was regulated through the IL23 pathway. Antagomir inhibition of miR-223 reactivated CLDN8 and improved a number of signs associated with TNBS-induced colitis in mice. Our study characterizes a new mechanistic pathway in IBD, in which miR-223 interacts with the IL23 pathway by targeting CLDN8. Strategies designed to disrupt this interaction may provide novel therapeutic agents for the management of IBD.
Surgery or Medical Therapy for Obese Patients with Type 2 Diabetes?
Authors: Paul Zimmet, K. George M.M. Alberti
Journal: New England Journal of Medicine (2012)

Type 2 diabetes is one of the fastest growing epidemics in human history and is closely associated with obesity.1 Furthermore, the disease has multiple manifestations and is associated with progressive beta-cell failure.2 Although lifestyle measures, including weight loss and physical activity, should be first-line treatment, success is difficult to achieve, and pharmaceutical intervention is almost always required.Because of the multiplicity of causal factors involved, it is unrealistic to expect that a patient will achieve excellent glycemic control with any single oral hypoglycemic agent or any combination of agents.3 The progressive nature of type 2 diabetes requires ongoing assessment of . . .
BI-30 * CHARACTERIZATION OF L1CAM AS A CLINICAL MARKER FOR THE C11orf95-RELA FUSION IN SUPRATENTORIAL EPENDYMOMAS
Authors: K. Wani, T. S. Armstrong, D. T. Jones, E. Vera-Bolanos, H. Witt, D. Capper, S. M. Pfister, R. J. Gilbertson, M. R. Gilbert, K. Aldape
Journal: Neuro-Oncology (2014)

BACKGROUND: Recently, a novel oncogenic fusion involving C11orf95 and RELA genes was described in a subset of supratentorial ependymoma causing aberrant activation of the NF-κB pathway. METHODS: We evaluated a cohort of 83 supratentorial ependymomas from the CERN tissue repository using RNAseq, RT-PCR and Illumina 450k profiling. RESULTS: RNAseq expression profiling identified L1CAM, a neuronal cell adhesion protein, as the most differentially expressed gene between fusion-positive and fusion-negative cases, with a 200 fold higher expression in the fusion-positive subgroup. Testing for the 2 most common fusion types showed positivity in 29/83 cases for an aberrant transcript and L1CAM IHC showed a concordance between IHC and fusion transcript status (positive IHC/fusion positive and negative IHC/fusion-negative) in 58/83 cases. Since prior work has shown a relationship between global methylation profile and fusion status, genome-wide DNA methylation (Illumina, 450K) was performed on a subset of 71 of the 83 cases and of these 38/71 showed methylation profiles consistent with the presence of a fusion-positive tumor. Concordance of predicted fusion with L1CAM IHC was very high, with 66/71 cases showing concordance of positive staining with predicted fusion and negative staining with absence of fusion. As a test case, we recently were made aware of a case of malignant sarcoma in a patient with a prior supratentorial ependymoma. L1CAM staining was positive, as was L1CAM IHC from the original ependymoma from the same patient, suggesting that the sarcoma-like recurrent tumor likely derived from the ependymoma. Sanger sequencing of the DNA from both the tumors confirmed the presence of the fusion, indicating potential utility of the L1CAM IHC marker. CONCLUSION: This study provides preliminary evidence for the use of L1CAM as a surrogate marker for the presence of the C11orf95-RELA fusion in supratentorial ependymoma that can be considered in a clinical diagnostic lab setting.
Studies of Food-Intake Regulation in Man
Authors: Robert G. Campbell, Sami A. Hashim, Theodore B. Van Itallie
Journal: New England Journal of Medicine (1971)

The effect on spontaneous food intake of concealed variations in nutritive density of machine-dispensed liquid diet was studied in five lean and four obese young adults and two obese juvenile subjects. They were unaware of the changes in caloric concentration and that food intake was being monitored. The lean subjects maintained weight during machine feeding, and when nutritive density was altered, promptly adjusted the volume consumed to maintain near constant energy intake. The obese adults ingested a small fraction of the calories needed to maintain weight and failed to adapt volume intake to appreciable changes in caloric concentration. The obese juvenile subjects consumed large quantities of formula however, one also failed to adjust volume intake when caloric density was varied. Lean young adults appear to regulate energy intake at the physiologic level when the nutritive concentration of the diet is altered covertly. Grossly obese adults seem incapable of such regulation.
OC-077 Jejunal tube feeding experience in paediatric nutrition support
Authors: C E Paxton, P M Gillett, G Wilkinson, F D Munro, S McGurk, K Armstrong, L Bremner, V Robb, J E Livingstone, D A Devadason, D J Mitchell, D C Wilson
Journal: Gut (2012)

<h3>Introduction</h3> There is an emerging group of children in whom poor and worsening upper GI dysmotility limits feed toleration and impacts growth; we wished to evaluate the role of jejunal tube feeding (JTF) in this group. <h3>Methods</h3> A retrospective cohort study (database/clinical note review) in a tertiary paediatric centre to evaluate use of PEG-J, transgastric gastrojejunostomy (GJ) tubes and surgical roux-en Y jejunostomy (ReYJ), and the impact on growth of JTF in children with worsening GI dysmotility. All children (&lt;18 years) receiving home enteral tube feeding (HETF) during the period 01 January 2002–31 December 2011. Weight at time of commencing JTF and at 6 or 12 months post-start was collected and expressed as SD or Z-score. Change in weight Z-score was calculated using paired t-test. <h3>Results</h3> A total of 866 children received HETF during the study period, of whom 41(5%) had JTF at home. Median (range) decimal age at start of JTF was 2.7(0.1–16.2) years. 36 of 41 (88%) had an underlying neurodisability; 33 of 41 (80%) were gastrostomy fed prior to commencing JTF. Of the 41 JTF children, 19 (46%) were fed via a GJ tube, 5 (12%) via PEG-J and 17 (42%) had a ReYJ. The majority of JTF related complications occurred with GJ tubes; although usually minor, one death occurred following small bowel intussusception around a GJ tube. Minor JTF complications included burst balloons, holes in the Y-port or tube and fungal infection and resolution required tube changes. Tube migration was a problem with both GJ and PEG-J tubes; ReYJ were associated with the fewest minor complications of stomal infection and leakage. By study end, 21 (51%) continue on JTF, 9 (22%) died (all but 1 due to their underlying condition), 1 (2%) moved out of area, 2 (5%) transitioned to adult services and 8 (20%) returned to gastric feeding. 25 of 41 children had JTF for &gt;6 months and had longitudinal growth data collected; median (range) weight Z-score at the start of JTF was −1.3 (−5.2–2.1) and rose to −1.0 (−3.4–2.3) by 6–12 months, with a significant improvement in mean (95% CI) change in weight Z-score of 0.7 (0.1 to 1.3) (p=0.02). <h3>Conclusion</h3> There are time consuming practical challenges associated with JTF, some of which are device dependent, and ReY JTF appears best for long-term usage. JTF is an effective intervention to improve growth in children with severe and worsening upper GI dysmotility. <h3>Competing interests</h3> None declared.
THU0081 Assessing the cardiovascular risk burden in patients with rheumatoid arthritis: Role of annual review clinic
Authors: V. Patel, U. Karjigi, R. Abernethy, J. Dawson, A. Clewes, J. Novak, A. Cox, J. Williams, T. O’Rourke
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is associated with the increased risk of cardiovascular (CV) mortality and morbidity [1]. There are recommendations by European League against Rheumatism (EULAR) and National Institute for Health and Clinical Excellence (NICE) to include assessment of cardiovascular, osteoporosis, infection and depression risks annually [2,3]. One of the ways CV risk is calculated is by assessing the 10-year risk of having CV event [4]. <h3>Objectives</h3> The objective was to determine the relationship of the traditional CV risk factors and compare with RA patients on disease modifying agents (DMARDs) and biologics therapy. <h3>Methods</h3> Data was collected retrospectively using a standardised data collection tool for all the 231 patients who attended the annual review clinics in the last 4 year from Aug 2006 to Aug 2011. Data was analysed by Fisher Exact test for discrete values and unpaired t-test for non-discrete values. <h3>Results</h3> The demographic characteristics of patients are shown in the table 1. The prevalence of various risk factors and CV risk in biological and DMARD patients are mentioned in table 2. <h3>Conclusions</h3> A multi-disciplinary annual review clinic allows assessing and predicting the CV risks. Our audit shows CV risk is prevalent in RA patients treated with DMARDS, which warrants regular screening. The CV risk was 23% in overall patients and it was 7% and 30% in biologics and DMARD patient’s respectively. This is the first study to show reduced CV risk in patients treated with biological therapy, most probably through the known beneficial effects on metabolism. We need further studies to confirm that the patients on biologics have lesser CV risk and to see if this translates into reduced cardiovascular disease in the long term. <h3>References</h3> Aho K, HeliovaaraM. Risk factors for rheumatoid arthritis. Ann Med 2004; 36:242–51. Peters MJ et al: EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010, 69:325–31 NICE guidelines: www.nice.org.uk/CG67 JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91(Suppl. 5):V1–52. <h3>Disclosure of Interest</h3> None Declared
Hepatic injury following colonoscopy
Authors: I. Noreña, A. Varón, C. Dennis, R. Dennis
Journal: Endoscopy (2013)

Colonoscopy is a common and relatively safe diagnostic and therapeutic procedure. Iatrogenic injuries have been reported in the medical literature, but the overall risk of serious complications such as perforations and visceral lacerations is low [1] [2] [3] [4]. Database studies have shown the total complication rate to be in the range of 2.8 per 1000 colonoscopies, with a mortality rate of 0.007 % [5].
A1.06 Phagocyte involvement in systemic onset juvenile idiopathic arthritis
Authors: NM ter Haar, W de Jager, RS Scholman, J Meerding, T Tak, PHC Leliefeld, SJ Vastert, S de Roock
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Systemic onset Juvenile Idiopathic Artritis (sJIA) is a systemic autoinflammatory disease, characterised by arthritis, spiking fever and rash and elevation of serum S100-proteins and interleukin (IL)-18. The role of monocytes and neutrophils in the inflammatory cascade of sJIA is still unclear. <h3>Objective</h3> To study the role of monocytes and neutrophils in the inflammatory cascade of sJIA. <h3>Methods</h3> We determined neutrophil activation <i><i>ex vivo</i></i> (phenotype and cell membrane markers) and after stimulation (ROS-production and degranulation) of cells derived from sJIA with disease onset or in remission, compared to healthy donors (HDs). To investigate the role of monocytes, we assessed cytokine production of PBMCs from sJIA patients and HDs after stimulation with TLR-4 activating S100-proteins (+/- ATP) or other TLR-ligands. In a cohort of sJIA patients at onset and during inactive disease, we evaluated cell counts and serum levels of cytokines, chemokines and other analytes. Cytokine concentrations in supernatant and serum were determined by multiplex immunoassay. <h3>Results</h3> Twenty-one of 23 patients with onset sJIA had elevated neutrophil counts, while monocyte counts were elevated in only 5/23 patients. Many inflammatory markers were significantly elevated in serum of onset sJIA patients, among which several neutrophil specific proteins indicating the importance of this cell type. Neutrophils from onset sJIA patients showed an activated phenotype, reflected by higher<i><i>ex vivo</i></i>cell membraneexpression of FC-gamma receptors (CD32 and CD64), markers of secretory vesicles (CD35) and specific granules (CD66b). ROS production and degranulation were also enhanced in onset sJIA. Neutrophil phenotypenormalized when patients were in remission. In contrast to the hyperactivated status of neutrophils in active sJIA, PBMCs from these patients produced less Il-1b, IL-18, IL-6 and TNF-a upon TLR-stimulation compared to PBMCs from remission patients or HDs, suggesting tolerance after exposure to high TLR4 stimulating S100-levels&nbsp;<i>in vivo</i>. <h3>Conclusions</h3> We show here that monocytes from onset sJIA patients produce less cytokines upon stimulation, while the neutrophils are hyperactivated, reflected by increased cell membrane activation markers, ROS production and degranulation. The exact role of each cell type and activity and their interaction in sJIA pathology is currently under investigation.
Pleural Leak Localization With Tc-99m Pentetate Aerosol in an AIDS Patient With Pneumocystis Carinii Pneumonia
Authors: JAMES P. CARTLAND, BARBARA BENSON
Journal: Clinical Nuclear Medicine (1996)

A 40-year-old man with AIDS and Pneumocystis carinii pneumonia had a large left pneumothorax. A 25-day course of conservative treatment with a chest tube failed because of a persistent air leak. Tc-99m pentetate aerosol was administered to localize the pleural leak and help plan surgical intervention. Images obtained immediately after administration of aerosolized Tc-99m pentetate show an area of greatly increased radionuclide activity in the apex of the left chest. Repair of a visualized left apical bleb was subsequently accomplished at thoracoscopy. Postsurgical chest x-rays demonstrated no residual or recurrent pneumothorax.
SP0064 Imaging Biomarkers as A Useful Tool in Gout Disease
Authors: B. Manger
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> Conventional radiography can show characteristic features of gouty arthritis such as intraosseous cysts or large erosions with overhanging edges in an advanced tophaceous stage. For early diagnosis, however, conventional X-rays are non-specific. Musculoskeletal ultrasound has the potential to support the non-invasive diagnosis of gouty arthritis. Sonography can detect free-floating MSU crystals in synovial fluid ("snow storm appearance") or subclinical tophaceous deposits. The most specific ultrasonographic finding, however, is the double contour sign, representing MSU deposits on the surface of hyaline cartilage (e. g. of femoral condyles or metatarsal heads). Numerous studies have demonstrated that sonography gives reproducible, sensitive, and specific results in the diagnosis of gouty arthritis. A recent study has examined, which combination of joint, cartilage, and tendon sites should be examined to get the best diagnostic information in patients with this disease. MRI is able to pick up synovitis, bone edema and erosions in gout with high sensitivity, but does not provide characteristic features to differentiate these from other forms of arthritis in early stages. Therefore, MRI does currently not offer a clear advantage to sonography in the diagnosis of gouty arthritis. Recently, yet another diagnostic method has been described, which allows non-invasive identification of sodium urate crystals deposits in the periarticular tissues. Dual energy computed tomography (DECT) is an imaging method, which uses X-ray beams of two different energies to differentiate solid sodium urate deposits from connective tissues and from calcium containing structures by their absorption properties. Several clinical studies could clearly demonstrate that DECT does not only reliably detect clinically overt tophi, but also detects subclinical urate deposition at periarticular or peritendinous sites in gout patients. Therefore, DECT may not only be a very helpful imaging method for tophus assessment and follow-up in clinical trials and during urate lowering therapy in patients with the established diagnosis of chronic gout. It may also be valuable as differential diagnostic tool in patients with "unclassified" acute or relapsing arthritides, when aspiration of synovial fluid is not possible or not successful. <h3>Disclosure of Interest</h3> B. Manger Consultant for: Berlin-Chemie, Astra-Zeneca, Savient <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6114
ASSOCIATION OF INSURANCE TYPE WITH RECEIPT OF ORAL ANTICOAGULATION IN ATRIAL FIBRILLATION: AN ANALYSIS OF THE AMERICAN COLLEGE OF CARDIOLOGY NCDR PINNACLE REGISTRY
Authors: Celina M. Yong, Yuyin Liu, Lanyu Lei, Gheorghe Doros, Christopher Cannon, Tom Maddox, Anil Gehi, Salim Virani, Mintu Turakhia
Journal: Journal of the American College of Cardiology (2016)