tbuckley/cabot-search huggingface dataset:
PTU-065 Long term outcomes of liver transplantation for Wilson's disease: a single centre experience
Authors: H Al-Hilou, S Hebbar, B K Gunson, L C Claridge, W-K Syn, A P Holt
Journal: Gut (2012)

<h3>Introduction</h3> Wilson9s disease is an autosomal recessive disorder of copper metabolism which may manifest as acute or chronic liver disease and/or neuropsychiatric disorders. Orthotopic liver transplantation (OLT) is life saving when performed for acute liver failure or end-stage liver disease but there are conflicting reports on the effects of OLT on neuropsychiatric symptoms. Furthermore, a recent report from an Italian group has highlighted poor outcomes following OLT in those with neuropsychiatric symptoms. <h3>Aim</h3> To evaluate the indications and outcomes of OLT for patients with Wilson9s disease and in particular to assess the effects of OLT on neuropsychiatric symptoms, and whether these disorders are associated with poor outcomes. <h3>Methods</h3> Data were acquired by retrospective analysis of case notes and databases. <h3>Results</h3> 21 adults with Wilson9s disease have been transplanted in Birmingham between 1987 and 2011. 53.3 % (11/21) were performed for acute liver failure and 42.8% (9/21) for decompensated cirrhosis. One patient was transplanted due to hepatocellular carcinoma. Median age was 19.5 at diagnosis and 25 at time of OLT. 10 patients had neuropsychiatric symptoms prior to OLT (Parkinsonism in three patients, anxiety in two patients, epilepsy, OCD, depression, ataxia and migraine). These symptoms resolved in 4/10 post-OLT. However, four patients developed new onset neuropsychiatric symptoms within 2 weeks of OLT; two patients had seizures, one developed psychosis and another became euphoric. Kayser–Fleisher (KF) rings are purportedly associated with neuropsychiatric disorders; in our cohort 61.9% (13/21) of patients had KF rings and 11/13 of these had neuropsychiatric symptoms. Four patients had significant post-operative complications comprising four haemorrhagic episodes and two biliary leaks. Actuarial survival rates were 95% at both 1 and 5 years. One patient died within 3 months of OLT and three patients died &gt;10 years post OLT. 3/4 deaths were due to multi-organ failure secondary to sepsis. Graft survival was 90% at 1 year and 81% at 5 years. Five patients have required re-grafting; three due to chronic rejection and two due to hepatic artery thrombosis. There were no appreciable differences in long term outcomes between those with and without pre-existing neuropsychiatric symptoms; 2/4 deaths and 2/5 re-grafts were in those with neuropsychiatric manifestations. <h3>Conclusion</h3> Outcomes of OLT for Wilson9s disease are comparable to transplantation for other diagnoses. Neuropsychiatric symptoms improved in &lt;50% of patients post-OLT and may also occur for the first time following OLT. At our centre pre-existing neuropsychiatric symptoms were not associated with poor outcomes. <h3>Competing interests</h3> None declared.
Abstract 1882: Gemcitabine pathway SNPs are associated with its PK parameters in patients with solid tumors
Authors: Amit K. Mitra, Amit Khatri, Mark N. Kirstein, Robert A. Kratzke, Jatinder K. Lamba
Journal: Cancer Research (2012)

Abstract Gemcitabine (2′, 2′-difluoro 2′-deoxycytidine, dFdC) is a cytotoxic pyrimidine antimetabolite used as first-line chemotherapeutic agent for the treatment of a wide range of solid tumors and hematologic malignancies. It is as a pro-drug that undergoes cellular uptake through transporters like human equilibrative nucleoside transporter (hENT1/SLC29A1) and human concentrative nucleoside transporters (hCNT1/SLC28A1 and hCNT3/SLC28A3) followed by extensive intracellular phosphorylation by kinases like deoxycytidine kinase (DCK) and cytidine monophosphate kinase (CMPK) to its active diphosphorylated (dFdCDP) and triphosphorylated (dFdCTP) forms. Gemcitabine is primarily inactivated via deamination to its less potent metabolite 2′, 2′-difluorodeoxyuridine (dFdU) by cytidine deaminase (CDA). High inter-patient variability in response to gemcitabine treatment has been a major concern in gemcitabine chemotherapy. However, association of pharmacogenomics with gemcitabine pharmacokinetics (PK) has not been extensively studied so far. In the present study, therefore, we investigated association between single nucleotide polymorphisms (SNPs) within genes involved in gemcitabine transport/metabolic pathway and pharmacokinetic parameter estimates for gemcitabine and metabolites in patients diagnosed with solid tumors. Pharmacokinetic blood sampling (n=40) was as follows: pre-infusion, 5, 15, 30, 45 min, and 1, 1.25, 1.5, 2, 6, 24, 48 and 72 hours after the end of gemcitabine infusion. Gemcitabine and dFdU concentrations in plasma and intracellular dFdCTP levels in PBMCs were measured using HPLC-UV and LC MS/MS. A total of 86 SNPs in 14 genes viz. CDA, CMPK, CTPS, DCK, DCTD, NME1, NME2, NME3, NME4, NT5C2, NT5C3, SLC28A1, SLC28A3, and SLC29A1 were genotyped using Sequenom-based assays. Pharmacogenomic association was evaluated using Wilcoxon rank-sum test and Kruskal-Wallis one-way analysis of variance by ranks (p≤0.05). SNPs in 5′ nucleotidase genes- rs1163075, rs1926029, rs11598702 and rs1712517 in NT5C2 and rs3750117 in NT5C3 were associated with gemcitabine elimination clearance. SNPs in CDA- rs1048977 and rs4655226 were associated with dFdU clearance. SNPs in CTPS- rs4430318, rs61780437 and rs1044457 were strongly associated with higher dFdCTP formation clearance. Additionally, CDA, DCTD, SLC28A1, SLC28A3 and SLC29A1 SNPs were also associated with dFdCTP formation clearance. The results from our study indicate pharmacogenomic association between gemcitabine pharmacokinetic pathway SNPs and PK parameters. Presence of these SNPs could impact outcomes for patients receiving gemcitabine therapy. 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 1882. doi:1538-7445.AM2012-1882
ME-04 * SUBVENTRICULAR SPREAD OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: V. Caretti, M. Bugiani, M. Freret, P. Schellen, M. Jansen, D. van Vuurden, G. Kaspers, P. G. Fisher, E. Hulleman, P. Wesseling, H. Vogel, M. Monje
Journal: Neuro-Oncology (2014)

Diffuse intrinsic pontine glioma (DIPG) is the second most common malignant pediatric brain tumor and the leading cause of brain tumor death in childhood. Standard therapy consisting of local radiotherapy to a dosage of 54-60 Gy extends median survival from 5 months to ∼9 months; 5-year survival remains less than 1%. Here, we report an autopsy series of 16 patients evaluated from 2009–2014 at Stanford (n = 10) and VU (n = 6) University Medical Centers. Consistent with previous reports, we found widespread dissemination of DIPG with extension to midbrain and medulla in 63%, cerebellum in 56%, thalamus in 56%, frontal cortex in 25% and supratentorial leptomeninges in 25%. The spinal cord was not consistently examined, but intramedullary spinal cord metastases were found in 2 of 3 cases examined; both had clinical evidence of spinal cord spread. A previously under-recognized pattern of subventricular spread was noted in 10/16 cases, with infiltration of the subventricular zone (SVZ) and tumor nodules in the frontal horns of the lateral ventricles. In three cases lateral ventricular disease was noted on pre-mortem MRI, but subclinical tumor invasion in the SVZ of the lateral ventricles was found in 6 additional cases; subventricular spread was found in the third ventricle of one additional case. This study demonstrates subventricular tumor spread in the majority of patients, typically later in the course of their disease. Thus as future therapies evolve to control local disease, strategies including extended or whole brain irradiation may become crucial. The patterns of widespread dissemination, including leptomeningeal, direct extension and subventricular spread, suggest that the extent of the optimal radiation field should be re-examined.
AB0341 Visualisation of the fifth metatarsophalangeal joint in patients with rheumatoid arthritis: Comparative pilot study using ultrasonography and magnetic resonance imaging in detection of the synovitis and erosions
Authors: V. Skakic, S. Aleksandra, S. Bozilov, A. Skakic
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To compare ultrasound (US) with magnetic resonance imaging (MRI), which was taken as a “gold standard” for detection of fifth metatarsophalangeal joint synovitis and erosions in patients diagnosed with RA (ACR). <h3>Methods</h3> Patients in Institute “Niska Banja” (n=44) with RA (ACR criteria dg) with clinical symptoms in both fifth metatarsophalangeal joints (n=88). 99% of women, mean age 55,1 and disease duration 6,3 years, included in our study. Ultrasonographicaly, using Esoate- My Lab 60 system, equipped with 10-13 MHz probe, have been visualised both fifth metatarsophalangeal joints, and then were reffered for MRI of the same joints on Arthroscen type M (0,2 T) machine. US was developed as the first method, and interpreted by one investigator, and then the other researcher, regardless of previous results of US findings, interpreted the MRI findings. The percentage of compatibility between methods, as well as sensitivity and specificity of US compared to the MRI as a “gold standard”, were examined by using a statistical methods. <h3>Results</h3> Compared with the MRI, as a gold standard, US in detection of fifth metatarsal joint synovitis has 92,86% sensitivity and specificity of 100%. US in detection of fifth metatarsal joint erosion has a sensitivity of 72,73%, and 81,82% specificity. The percentage of compatibility between US and MRI, as golden standard methods, was statistically significant. As for the detection of synovitis, according to Cochen kappa test compatibility was highly statistically significant: kappa test 0,904 (p&lt;0,0001). When it comes to erosions, compatibility was smaller but still statistically significant: kappa test 0,545 (p=0,01). <h3>Conclusions</h3> US is sensitive method in fifth metatarsophalangeal joint pathology detection, when it comes to detection of synovitis and erosions in patients with RA, compared with MRI as gold standard. Nevertheless, this study shows that further development of US examination techniques and the use of higher frequency probes is necessary, specially in detection of metatarsophalangeal joints erosive changes. <h3>Disclosure of Interest</h3> None Declared
Preventive effects of the EGFr inhibitor erlotinib in ER+ methylnitrosourea (MNU) induced and in ER- MMTV/Neu/P53KO mammary cancer models.
Authors: CJ Grubbs, KK Iwata, E Buck, M Juliana, RA Lubet
Journal: Cancer Research (2009)

Abstract Abstract #1112 The preventive/therapeutic efficacies of Erlotinib in both ER+ and ER- models of breast cancer in rats and mice, respectively, were evaluated. For the ER+ model, female Sprague-Dawley rats were administered MNU at 50 days of age. Beginning five days later, Erlotinib was administered 7x/week for the remainder of the study. Daily administration of Erlotinib in a prevention setting at 4 and 1.33 mg/kg BW/day reduced tumor multiplicity by 72 and 35%, respectively; doses &amp;gt;6 mg/kg BW/day decreased cancers by &amp;gt;90%. When rats with palpable mammary cancers were treated for six weeks with 4 mg/kg BW/day of Erlotinib, most of the tumors showed highly significantly regressions. Similarly, when rats bearing palpable mammary cancers were treated with Erlotinib for 5 days (3 or 1 mg/kg BW/day), large decreases in tumor cell proliferation and alterations in expression of phosphorylated EGFr, AKT, ERK and SHC were observed. In additional studies, the preventive effect of Erlotinib in a MMTV/Neu/P53KO bitransgenic model was examined. These mice develop ER- cancers which overexpress Neu and have an alteration in P53. These changes are characteristic of ER- human breast cancers. An initial experiment showed that Erlotinib (50 mg/Kg BW/day) was also effective as a preventive agent in this model. Effects of this agent on proliferation and altered expression of phosphorylated EGFr, AKT, ERK and SHC are in progress. Our results showing efficacy of the EGFr inhibitor Erlotinib in ER+ mammary cancers are in agreement with a clinical study of early stage human ER+ breast cancer showing that the EGFr inhibitor Gefitinib is highly effective in ER+/EGFr+ tumors (Polychronis, et al., Lancet Oncolo. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1112.
1971-1991: Science Unlocks Cancer Cell Secrets
Authors: P. A. Newman
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article 1971–1991: Science Unlocks Cancer Cell Secrets Get access Patricia A. Newman Patricia A. Newman Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 2, 16 January 1991, Pages 84–86, https://doi.org/10.1093/jnci/83.2.84 Published: 16 January 1991
THU0296 Matrix interference of IL-6, IL-17, IL-21 and TNF-alpha measurement in juvenile-onset systemic lupus erythematosus serum and plasma:
Authors: J. Ong, D. Harris, G. Jeffers, L. Watson, L. Ballantine, M. Beresford
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Abnormal cytokine expression is postulated to be a factor in the immunopathology of Systemic Lupus Erythematosus (SLE), leading to inflammation and organ damage. Several studies have shown elevated levels of IL-6, IL-17, IL-21 and TNF-α in adult SLE serum and plasma using ELISAs<sup>1,2</sup>. A spike-and-recovery assessment is used to measure the analyte recovery difference between a natural sample matrix and the standard diluent. Generally 80-120% is considered an acceptable range of recovery. A previous spike-and-recovery study of SLE serum and plasma has shown poor recovery of high mobility group box 1 (HMGB1) protein<sup>3</sup>. <h3>Objectives</h3> To validate and assess the assay response of juvenile-onset SLE (JSLE) serum and plasma in IL-6, IL-17, IL-21 and TNF-α detection kits. <h3>Methods</h3> JSLE plasma and serum samples were assayed in spike-and-recovery and linearity-dilution experiments. Three spike-and-recovery ELISA assessments with IL-21 (Biolegend), IL-6 and TNF-α (R&amp;D Systems) were performed, each including 3 JSLE plasma samples and 1 control sample. IL-17 spike-and-recovery ELISA (eBioscience) was executed with 2 JSLE serum and 2 JSLE plasma samples. A spike-and-recovery assessment with IL-17 was performed on 5 JSLE serum samples using a single Bio-Plex Assay (Bio-Rad). Percentage recovery of respective cytokines in spiked and unspiked samples were then calculated and compared against the concentration of spiked sample diluents. <h3>Results</h3> Recovery percentages in JSLE samples were less than 80% in TNF-α, IL-17 and IL-21 assays (Fig. 1), apart from IL-17 and TNF-α at 1 in 8 dilution which yielded 80% and 113% respectively. Measuring IL-21 in JSLE and control samples showed poor recovery out of acceptable range at all 4 dilutions. IL-6 concentrations fell within the acceptable range and demonstrated good responses in JSLE and control samples. <h3>Conclusions</h3> Interference was observed in the assay response of JSLE serum and plasma in IL-17, IL-21 and TNF-α assays but not IL-6 ELISA. Recovery increased with sample matrix dilution, indicating that dilution reduced the interference, however this must be balanced against the risk of diluting out the analyte. It can be inferred that constituents in the sample matrix may be affecting the detection of these cytokines. JSLE plasma/serum cytokine concentrations measured by ELISA and single plex assays must be interpreted with caution. Methods such as using specialist buffers or alternative assays should be considered to minimise interference and to increase robustness of future studies. Spike-recovery experiments using a multiplex assay platform are currently underway. <h3>References</h3> Ohl K et al. J Biomed Biotechnol. 2011;2011. Davas EM et al. Clin Rheumatol. 1999;18(1):17-22. Urbonaviciute V et al. J Leukoc Biol. 2007;81(1):67-74. <h3>Disclosure of Interest</h3> None Declared
Induction of Labor as Compared with Serial Antenatal Monitoring in Post-Term Pregnancy
Authors: Mary E. Hannah, Walter J. Hannah, Jonathan Hellmann, Sheila Hewson, Ruth Milner, Andrew Willan
Journal: New England Journal of Medicine (1992)

The rates of perinatal mortality and neonatal morbidity are higher for post-term pregnancies than for term pregnancies. It is not known, however, whether the induction of labor results in better outcomes than does serial fetal monitoring while awaiting spontaneous labor.
Abstract 1982: TGF-beta induced SIK cooperates with Smurf2 to negatively regulate type I receptor kinase signaling
Authors: Michael Vanlandewijck, Peter Lönn, Marcin Kowanetz, Katarzyna Kowanetz, Christer Bush, Carl-Henrik Heldin, Aristidis Moustakas
Journal: Cancer Research (2011)

Abstract Signal transduction pathways, like transforming growth factor beta (TGFβ), regulate many physiological processes and require control mechanisms to safeguard proper and timely action. Dysregulation of TGFβ signaling is established as a major player in cancer progression. We have recently described how negative regulation of TGFβ signaling is controlled by the serine/threonine kinase salt-inducible kinase (SIK). SIK is induced by TGFβ and forms protein complexes with the TGFβ type I receptor and with the inhibitory Smad7, which leads to type I receptor downregulation. We now investigate this mechanism further and demonstrate similarities between TGFβ/Smad-mediated immediate-early induction of SIK and Smad7. We also relate another protein of the negative feedback loop of TGFβ signaling, the E3 ubiquitin ligase Smurf2, to this mechanism of regulation. We provide evidence that Smurf2 cooperates with SIK to downregulate the type I receptor. Both the kinase activity of SIK and the ubiquitin ligase activity of Smurf2 are important for proper receptor turnover. However, Smurf2 does not directly bind to SIK, but participates in the complex via the PY-motif of Smad7. We thus establish a central role for Smad7 during SIK-mediated receptor downregulation. Finally, we explore the role of SIK in a cancer context by investigating its expression profile in human prostate cancer tissues. In conclusion, we have uncovered a phosphorylation/ubiquitination-dependent mechanism for TGFβ receptor downregulation that could play important roles during cancer progression. 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 1982. doi:10.1158/1538-7445.AM2011-1982
Phimosis Revealed by Contamination with Radioactive Urine on Bone Scintigraphy
Authors: S T Lim, M H Sohn, J Y Kwak, C Y Yim
Journal: Clinical Nuclear Medicine (2001)

TAE LIM, SEOK M.D.*; SOHN, MYUNG-HEE M.D.*‡; KWAK, JAE-YONG M.D.†‡; YIM, CHANG-YEOL M.D.†‡ Author Information
SP0068 Osteoblasts in Bone Growth, Homeostasis and Repair
Authors: C. Maes
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Despite the great variety of shapes and sizes, bones develop and grow through a small number of cellular mechanisms. The most common strategy, forming all the long bones of the axial (vertebrae, ribs) and appendicular skeleton (limbs), is endochondral ossification. In this process, mineralized bones form by organizing the cells and matrix of bone on scaffolding cartilage models. Absolute requirements for normal endochondral bone formation are, firstly, the provision of correctly positioned bone-forming osteoblasts and secondly, progressive neovascularization of the growing bone. We recently found that these two aspects go hand in hand. Using transgenic mouse models designed for lineage tracing of stage-selective osteogenic cells we found that specifically osteoprogenitors, and not mature osteoblasts, translocated from the perichondrium that envelopes developing bones, to initiate the ossification center inside the long bone shaft. They subsequently differentiated into mature bone-anchored osteoblasts forming trabecular bone, or remained part of the inter-trabecular immature osteogenic stroma. A similar angiogenic-osteogenic co-invasion occurred during fracture repair. Intriguingly, a subset of the osteoprogenitors that entered the developing and healing bone centers was found wrapped around the blood vessels as pericytes. This cellular interaction could possibly explain the tight spatio-temporal coupling between angiogenesis and osteogenesis that is seen in bone growth, homeostasis, repair and disease. Therefore, in our current and future work, we focus particularly on positional aspects of osteoblast lineage cells and the interplay between these cells and their microenvironment, including interactions with the endothelial cells of the bone and marrow vasculature. Using genetically altered mice as model organism, as well as in vitro and molecular approaches, we study the mechanisms regulating these processes and their significance for bone physiology and regeneration. Elucidating the cellular and molecular mechanisms underlying the spatial control of bone formation may pave the way to new or improved anabolic therapies for widespread skeletal pathologies such as osteoporosis and impaired fracture healing. <h3>Disclosure of Interest</h3> None Declared
P255 ATTAIN: twice-daily aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease
Authors: D. Singh, P. W. Jones, E. D. Bateman, A. Agusti, R. Lamarca, G. de Miquel, C. Caracta, E. Garcia Gil
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> The Phase III ATTAIN study investigated the effect of two twice daily doses of aclidinium bromide, a second-generation, long-acting muscarinic antagonist with low systemic activity, in patients with moderate to severe chronic obstructive pulmonary disease (COPD). <h3>Methods</h3> In this 24-week, double-blind study, patients were randomised (1:1:1) to receive aclidinium (200 μg, 400 μg) or placebo, twice daily. The primary endpoint was change from baseline in trough forced expiratory volume in 1 second (FEV<sub>1</sub>) at Week 24. Other study assessments at 24 weeks included: change from baseline in peak FEV<sub>1</sub>; percentage of patients achieving a clinically meaningful improvement in St George9s Respiratory Questionnaire total score and Transition Dyspnoea Index; COPD symptoms as assessed by the EXACT Respiratory Symptoms score; exacerbation rate based on two definitions (healthcare resource utilisation and EXAcerbations of Chronic pulmonary disease Tool). Adverse events (AEs), clinical laboratory measures, vital signs and ECGs were also assessed. <h3>Results</h3> A total of 819 patients were included in intention-to-treat (ITT) and safety populations. At Week 24, aclidinium 200 μg and 400 μg significantly improved trough FEV<sub>1</sub> from baseline compared with placebo (by 99 ml and 128 ml, respectively; both p&lt;0.0001). Aclidinium was significantly superior to placebo at Week 24 for all other study assessments (Abstract P255 table 1). Aclidinium was well tolerated and the incidence of anticholinergic AEs was low and similar to placebo. Changes in laboratory tests, vital signs and ECGs were similar between all groups. <h3>Conclusion</h3> Aclidinium 200 μg and 400 μg twice daily provided clinically meaningful improvements in bronchodilation, health status, symptoms, breathlessness and exacerbation rate. Aclidinium was well tolerated with a similar safety profile for both doses; the incidence of AEs was similar to placebo.