tbuckley/cabot-search huggingface dataset:
THU0193 Body Weight and Sex Influence the Pharmacokinetics of Adalimumab in Rheumatoid Arthritis
Authors: E. Ducourau, D. Ternant, T. Lequerre, P. Fuzibet, G. Paintaud, X. Le Loët, O. Vittecoq, P. Goupille, D. Mulleman
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). Subcutaneous injections of adalimumab lead to highly variable trough concentrations between patients [1] that may partly explain the variability of response. To date, adalimumab pharmacokinetics (PK) after subcutaneous route has never been described. <h3>Objectives</h3> The goal of this study is to analyse the quantitative influence of individual factors on adalimumab PK in RA patients. <h3>Methods</h3> One hundred and twenty seven samples from 30 RA patients were used to measure adalimumab concentration [in a post-hoc analysis]. All patients received adalimumab 40 mg subcutaneously every other week. CRP levels and RA disease activity score (DAS28) were available at baseline, weeks 6, 12, 24 and 52. Adalimumab PK was described using a single compartment model with first-order absorption and elimination rates. A population approach was used. Sex, age, body weight, corticosteroid use and CRP levels were tested as covariates on each pharmacokinetic parameter. <h3>Results</h3> The following pharmacokinetic parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd/F) = 12.4 L (75%), apparent clearance (CL/F) = 0.31 L/day (17%) and first-order absorption constant (k<sub>a</sub>) = 0.41 day<sup>-1</sup>. Apparent clearance increased with body weight and was higher in men. Age, CRP levels, and concomitant treatment with corticosteroid had no effect on pharmacokinetic parameters. Adalimumab concentrations reached steady state after 20 weeks in men and 28 weeks in women. <h3>Conclusions</h3> Men eliminate adalimumab faster than women and the rate of elimination increases with weight in RA. Monitoring of serum adalimumab concentrations may be useful to avoid underexposure and treatment failure. Time to steady state was long and raises the question of a loading dose of adalimumab at initiation. <h3>References</h3> Bartelds GM et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007; 66(7):921-926. <h3>Acknowledgements</h3> Pr Christian Marcelli, CHU Caen. Pr René-Marc Flipo, CHU Lille. Pr Patrice Fardellone, CHU d'Amiens <h3>Disclosure of Interest</h3> None Declared
PTU-142 Small bowel capsule endoscopy: a review of 232 studies undertaken at a single centre
Authors: A M Verma, R Ramiah, D Legge, A Dixon
Journal: Gut (2012)

<h3>Introduction</h3> Capsule endoscopy (CE) is the modality of choice for investigating small bowel pathology. It is non-invasive, tolerated, safe and reliable. The BSG have issued guidance on the use of CE for patients with obscure gastrointestinal bleeding (OGB) and for patients with a high suspicion of small bowel Crohn9s disease undetected by conventional means, in Kettering General Hospital (KGH) CE has been used extensively for this as MR enteroclysis is not available. KGH introduced a CE service in 2008. In 3+ years, 232 studies have been reported. KGH uses Diagmed/Given PillCam 2 CE. Patients take two sachets of Klean prep prior to their study. Patients do not undergo patency capsule testing. Patients take the capsule and using a laptop computer, a real time image is visualised, ensuring the capsule has passed into the small bowel. Patients are sent home and keep the recording belt and box on for 12–15 h. If capsule does not pass into small bowel patients are given a pro-kinetic and if that fails they undergo a gastroscopy to introduce the capsule into the distal duodenum (rarely required). <h3>Methods</h3> Demographic data, indications, quality of bowel preparation and diagnosis is recorded in a database. This has been analysed using Mircrosoft Excel. <h3>Results</h3> <b>Overall</b>: 232 studies, mean age = 54.93 years, median = 57.31 years. 114 males, mean age= 57.83 years, median = 60.80 years. 118 females, mean age = 52.07, median = 52.5 years. Yield of pathology = 100 studies (43.10%). 3 capsules retained (1.72%)—2 strictures, 1 trapped in diverticulum. <b>Obscure GI bleeding/anaemia as an indication</b>: 174 studies, yield = 72 studies (41.38%). Diagnoses: angioectasia 13, erosions/ulcers 11 (gastric 3), Crohn9s disease 6, tumours 6, active bleeding 5, polyps 5, stenosis/stricture = 5. <b>Other indications:</b> 58 studies: ?Crohn9s disease 46 (yield = 22/47.83%), known Crohn9s 6, abnormal imaging = 3, other = 3. <h3>Conclusion</h3> This series of CE studies reveals a yield of 43.10% with a low capsule retention rate of 1.73%. As these patients have had multiple investigations (endoscopies/cross sectional imaging) it suggests that in patients with suspected small bowel pathology, CE is very useful (with a high yield) and safe. For OGB the yield is 41.38% with common diagnoses being angioectasia, ulcers/erosions. Occasionally active bleeding, polyps and tumours are seen. This confirms the importance of CE in investigating OGB. For suspected Crohns9s disease the yield is high (47.83%). This confirms that as long as patients don9t have symptoms of sub-acute small bowel obstruction, CE is a very useful diagnostic modality for small bowel Crohn9s disease. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <b>Sidhu R</b>, Sanders DS, Morris AJ, <i>et al.</i> Guidelines on small bowel enteroscopy and capsule endoscopy in adults. <i>Gut</i> 2008;<b>57</b>:125–36.
ADVERSE EVENTS IN PATIENTS WITH LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS &lt;25 OR &lt;15 MG/DL ON AT LEAST TWO CONSECUTIVE VISITS IN FOURTEEN RANDOMIZED, CONTROLLED, CLINICAL TRIALS OF ALIROCUMAB
Authors: Jennifer Robinson, Michel Farnier, Umesh Chaudhari, Bill Sasiela, Christelle Lorenzato, Kathryn Miller, John J P Kastelein
Journal: Journal of the American College of Cardiology (2015)
The Pharmacology and Use of H<sub>1</sub>-Receptor-Antagonist Drugs
Authors: Alastair J.J. Wood, F. Estelle R. Simons, Keith J. Simons
Journal: New England Journal of Medicine (1994)

The H1-receptor antagonists are among the most widely used medications in the world. We review here the molecular basis of their action and their clinical pharmacology, efficacy in allergic disorders, and adverse effects. Although we will discuss the first-generation, relatively sedating H1-receptor antagonists briefly, we will emphasize the role of the second-generation, relatively nonsedating H1 antagonists (Figure 1) and will identify future directions for research of these agents.Molecular Basis of ActionHistamine mediates a variety of physiologic and pathologic responses in different tissues and cells and is an important chemical mediator of inflammation in . . .
Abstract 5424: Docosahexaenoic acid (DHA) induces gene expression of <i>RASSF1A</i> through epigenetics mechanisms in breast cancer cells
Authors: Rita de Cassia Borges de Castro, Danielle Fontes de Almeida, Graziela Rosa Ravacci, Rosimeire Aparecida Roela, Tatiane Katsue Furuya Mazzotti, Maria Mitzi Brentani, Aline De Conti, Thomas Prates Ong, Fernando Salvador Moreno, Dan Linetzky Waitzberg
Journal: Cancer Research (2012)

Abstract Background: Epigenetic changes, such as DNA methylation and post-translational histones modifications have an important role in mammary tumorigenesis. Changes in DNA methylation include global hypomethylation and hypermethylation of promoter regions of specific genes. Several genes are hypermethylated in breast cancer, especially the tumor suppressor gene RASSF1A, that have potential prognostic value. Epigenetic events are important as therapeutic targets due to its reversible feature. Dietary compounds can modulate the epigenetic processes in cancer. Experimentally, docosahexaenoic acid (DHA), a member of the omega-3 fatty acids, can reduce proliferation, induce apoptosis and decrease the invasive potential of breast tumor cells. However, the antitumor mechanisms of DHA and its ability to modulate epigenetic events are not yet fully elucidated. Objectives: To verify DHA action on RASSF1A expression and promoter region methylation in different human breast cancer cell lines. Material and Methods: Three different breast cell lines (MCF-7, MDA-MB-231, SKBR-3) were treated or not with 100 μM of DHA for 72 hours. Real time quantitative PCR were performed for gene expression quantification of RASSF1A. DNA methylation of the promoter region of RASSF1A was evaluated by methylation specific PCR. The western blot will be held for analyze of the histone 3 lysine 9 acetylated (H3K9ac) protein. Moreover, we will evaluate the phases of the cell cycle and apoptosis by flow cytometry. Results and Conclusion: Compared to control cells (not treated), DHA increased RASSF1A expression on MCF-7, but not in MDA-MB and in SKBR-3. These three transformed breast cells lines show methylation in specific region of RASSF1A promoter, indicating its role as a tumour supressing gene. DHA treatment increased RASSF1A promoter region hypomethylation in MCF-7, but not in MDA-MB and in SKBR-3. From this perspective, we can suggest that DHA could act by epigenetic mechanisms and reactivate RASSF1A, previously silenced. This action occured specifically in MCF-7, a less aggressive breast tumor cell line. It is expected that the present results promote better understanding of DHA role as a potential anti-oncogenic compound of breast cancer. 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 5424. doi:1538-7445.AM2012-5424
Mesenteric Lymphadenitis and Terminal Ileitis Due to<i>Yersinia pseudotuberculosis</i>
Authors: Jaroy Weber, Norris B. Finlayson, James B. D. Mark
Journal: New England Journal of Medicine (1970)

Two patients with a clinical picture of acute appendicitis were found to have mesenteric lymphadenitis and terminal ileitis due to Yersinia pseudotuberculosis. Human infection with Y. pseudotuberculosis has been reported frequently from Europe, but only rarely in this country. The disease is usually a self-limited one, although septicemia occurs occasionally. The organism is generally sensitive to streptomycin, kanamycin, tetracycline and ampicillin. More frequent cultures and serologic testing are encouraged in patients with mesenteric lymphadenitis and regional ileitis.
SAT0212 Circulating Endothelial Microparticles Reflect Microvascular Impairment in Patients with Systemic Sclerosis
Authors: O. Kowal-Bielecka, M. Bielecki, M. Michalska-Jakubus, D. Krasowska
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Endothelial injury plays a key role in the pathogenesis of systemic sclerosis (SSc), but its quantitative assessment has yet to be established clinically. Circulating endothelial microparticles (EMPs) are considered markers of endothelial state. <h3>Objectives</h3> This study was aimed to investigate possible relationships between circulating EMPs and clinical features as well as microvascular impairment assessed by nailfold capillaroscopy in patients with SSc. <h3>Methods</h3> 47 patients fulfilling the ACR classification criteria for SSc (40 with limited and 7 with diffuse for f the disease) and 27 age- and sex-matched healthy controls were included into the study. EMPs were identified with flow cytometry after staining platelet-poor plasma (PPP) with combinations of fluorescent cell-specific monoclonal antibodies (anti-CD31, -51, -42b, -62E and -AnnexinV). The following types of EMPs were evaluated: total EMPs (CD31+/CD42b-), activated EMPs (CD62E+/AnnV-,) and apoptotic EMPs (CD62E+/AnnV+ or CD51+). <h3>Results</h3> All types of EMPs were significantly elevated in SSc patients as compared with healthy controls - Table 1. No significant association could be found between EMPs levels and clinical or laboratory features of the disease including disease subtype, autoantibodies status, presence of digital ulcers, severity of skin and lung involvement or disease activity. Interestingly, concentration of total EMPs inversely correlated with the severity of capillary damage, as assessed by nailfold capillaroscopy. Accordingly, concentration of total EMPs was significantly lower in SSc patients with avascular areas (1731 +/- 1038 per mikroL of PPP) as compared with SSc patients without evidence of avascularisation (2639 +/- 1423 per mikroL of PPP, p&lt;0.05) and inversely correlated with avascularisation score (R= -0.34, p&lt;0.05). Number of bushy capillaries, which are believed to reflect neovascularization, significantly correlated with activated EMPs (R=0.32, p&lt;0.05) and inversely – with total EMPs (R= -0.37, p&lt;0.05). However, both these correlations lost their significance when corrected for the severity of avascularisation. <h3>Conclusions</h3> Our results indicate that numbers and phenotype of circulating EMPs might reflect microvascular impairments in SSc patients. In our study concentration of total EMPs appears to correlate with number of microvessels while concentration of activated EMPs seems more specificly reflect neovascularisation. <h3>Disclosure of Interest</h3> None Declared
Abstract C23: Epigenetic regulation of miRNAs and influence on malignancy in Ewing tumors
Authors: Guenther H.S. Richter, Stephanie Plehm, Stefan Burdach
Journal: Cancer Research (2011)

Abstract Although microRNAs (miRNA) were shown to be involved in cancer progression of many tumor entities, little is known about the role of non-coding RNAs in Ewing Tumor (ET) pathogenesis. The highly malignant ET comprise the second most common type of bone associated cancers in children and are characterized by oncogenic ews/ets translocations. We previously observed the histone methyltransferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be regulated by EWS-FLI1 and highly increased in ET. Here we demonstrate that EZH2 occupies promotor regions of putative tumor suppressor miRNAs and differentiation associated miRNAs in ET. We show that EZH2 mediates silencincig of miRNA expression via histone modification as well as DNA methylation and that these miRNAs are reactivated upon EZH2 knock down or treatment with inhibitors histone deacetylation and DNA methylation. In addition, we show that the well-known oncogenic miRNA221 is highly expressed in ET and processed in the presence of Argonaute (AGO) protein 2. Using RNA interference we observed that AGO1 and AGO2 mediated processes affect cellular invasiveness and anchorage-independent proliferation in vitro and influence ET growth and metastasis in immunodeficient Rag2−/−γC−/− mice, confirming an involvement of non-coding RNAs in ET pathogenesis. Taken together, these data illuminate the hitherto unknown epigenetic regulation of miRNA expression by EZH2 in ET and a general involvement of noncoding RNA in ET-pathogenesis, opening the avenue for new therapeutic modalities i.e. the implementation of miRNA therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C23.
HOW BRAIN LESIONS AFFECT NORMAL AND NEUROTIC BEHAVIOR
Authors: JULES H. MASSERMAN, CURTIS PECHTEL
Journal: American Journal of Psychiatry (1956)

Over a period of 6 years 50 cats and 40 monkeys were closely observed for (1) their individual and social characteristics; (2) their capacity to learn various skills; and (3) the form and persistence of the experimental neuroses induced in 23 cats and 18 monkeys by exposure to adaptational conflicts. The animals were then subjected severally to lesions of the anterior or mediodorsal thalamus, the amygdalae, or cerebral areas 13, 23, or 24. The results to date indicate that the general and specific effects of cerebral lesions vary not only with their site and extent but also with (1) the preoperative experiences of each animal and (2) its postoperative care and re-training.
Abstract 1922: Plasminogen activator inhibitor type-1 (PAI-1) enhances bladder cancer tumor progression.
Authors: Evan Gomes, Steven Goodison, Makito Miyake, Shanti Ross, Ge Zhang, Charles Rosser
Journal: Cancer Research (2013)

Abstract Introduction: Bladder cancer (BCa) is among the five most common malignancies worldwide and has the highest recurrence rate of any tumor type. BCa biology is poorly understood and early detection remains one of the most urgent issues in BCa research. Previously we have identified a preliminary molecular signature of BCa in voided urine samples from BCa patients. Our results revealed aberrant overexpression of the serine protease inhibitor (serpin) plasminogen activator inhibitor type-1 (PAI-1), both at the genomic and protein level. Increasing evidence indicate that elevated levels of PAI-1 correlates to a poor prognosis in many tumor types including breast, colorectal, gastric, ovarian, and more recently bladder cancer. PAI-1 has emerged as a potential target for BCa treatment and the aim of this study is to provide a greater understanding of its role in bladder cancer progression. Methods: PAI-1 expression levels in UROtsa (benign urothelial cell), KU7 (low-grade papillary urothelial cancer cell), and UMUC14 and T24 (high-grade invasive urothelial cancer cell lines) was tested by real-time PCR (RTPCR) and Western blot analysis. Secreted PAI-1 levels were measured by ELISA. KU7 stable clones overexpressing PAI-1 was established by transfection of plasmid DNA encoding human PAI-1. T24 and UMUC14 stable clones with shRNA knockdown of PAI-1 were established by infection with retroviral particles. Cell proliferation, migration, invasion, and apoptosis assays were performed in stable clones. Results: RTPCR analysis revealed an increase of PAI-1 in T24 and UMUC14 cells (27.9 and 5.2 times, respectively) while KU7 cells exhibited significantly reduced levels as compared to the UROtsa control. Similar results were observed for PAI-1 protein concentrations in cell culture supernatants and western blot analysis. While overexpression of PAI-1 in KU7 cells promoted an increase in proliferation, migration and invasion, these were significantly reduced upon inactivation of PAI-1 in T24 and UMUC14 cells stably expressing shRNA PAI-1. Loss of PAI-1 function also led to a substantial increase in apoptotic cell death. Conclusions: These results suggest that PAI-1 overexpression in BCa promotes tumor progression and therapeutic strategies targeting PAI-1 may serve clinically beneficial outcomes. Funding provided by research grants from Florida Department of Health James and Esther King Team Science Award 10KT-01 (CJR) and National Cancer Institute RO1 CA116161 (SG). Citation Format: Evan Gomes, Steven Goodison, Makito Miyake, Shanti Ross, Ge Zhang, Charles Rosser. Plasminogen activator inhibitor type-1 (PAI-1) enhances bladder cancer tumor progression. [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 1922. doi:10.1158/1538-7445.AM2013-1922
Abstract 237: Novel applications of pSIVA, a new polarity sensitive phosphatidylserine (PS) apoptosis/cell death probe
Authors: Lisa S. Stein, Payton D. Quintel, Stan Krajewski, Jonathan S. Rosenberg, Sujay K. Singh
Journal: Cancer Research (2012)

Abstract pSIVA is a newly developed Annexin B12 based polarity sensitive probe for monitoring exposed PS, a hallmark of apoptosis. A unique feature of pSIVA is that it fluoresces (green channel) only when bound to PS, and hence no wash steps are needed to remove unbound probe. This attribute is enabling the development of new methodologies not previously possible with classical Annexin V conjugates, which fluoresce irrespective of whether or not they are bound to PS. In this study we developed a flow cytometry protocol whereby pSIVA is added directly to cell culture media, avoiding the use of buffers. The protocol eliminates unforeseen perturbation or negative effects that standard buffers can have on sensitive cell types. Multicolor methodology that employed pSIVA-labeled cells along with intracellular markers was developed for flow cytometry and microscopy platforms. A model using primary mouse neurons labeled with pSIVA, DAPI and MAP2 (neuronal marker) indicated pSIVA stained the cell body of spontaneously dying neurons but stained both the cell body and degenerating axons in staurosporine treated neurons. These results suggest that mechanisms of PS exposure may vary between different apoptotic processes, including spontaneous versus induced apoptosis. They also suggest pSIVA has potential for elucidating new pathways of PS exposure heretofore not possible with existing reagents. 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 237. doi:1538-7445.AM2012-237