tbuckley/cabot-search huggingface dataset:
DR-03 * MECHANISMS THAT CAUSE RESISTANCE TO EGFR TARGETED THERAPIES IN GLIOMA
Authors: T. Johns
Journal: Neuro-Oncology (2014)

The epidermal growth factor receptor (EGFR), or its expression, is altered in 57% of glioma by mutation, rearrangement, altered splicing and/or focal amplification, suggesting that EGFR should be a prime target for therapy. However, attempts to therapeutically target EGFR in patients with glioma have so far failed. The fundamental reasons why EGFR inhibitors are so ineffective against glioma remain largely unknown. We used three approaches to address this question. First, we derived a range of early passage neurosphere cell lines from glioma patients. These cell lines express different forms of the mutated EGFR, including the most common alterations in glioma: the autoactivating deletion mutant EGFRvIII and the extracellular domain (ECD) point mutation A289V. Through exonic sequencing and signaling pathway analysis of these cell lines, several of which are resistant to EGFR-targeted therapeutics, we showed that activation of the ras/MEK/ERK signaling pathway led to innate resistance to EGFR-targeted drugs (to both tyrosine kinase inhibitors and EGFR-specific antibodies). Likewise, engagement of neurosphere cell lines with extracellular matrix proteins such as laminin caused resistance to EGFR-targeted therapeutics. Second, we analyzed a range of EGFR ECD cysteine mutants identified in glioma patient samples. All four mutants analyzed were found on the cell surface as inactive, preformed dimers. However, all receptor mutants had enhanced activation, as measured by autophosphorylation in response to EGFR ligands. Importantly, expression of these mutants in U87MG glioma xenografts rendered the tumors more susceptible to EGFR-targeted therapeutics than xenografts expressing wild-type EGFR. Last, we show that EGFRvIII partly mediates its tumorigenicity through promiscuous activation of other receptor tyrosine kinases, such as MET, through a FAK scaffold. Co-targeting the kinase activity of FAK significantly increased the antitumor activity of EGFR-targeted therapeutics. These studies provide new insight into the mechanisms of resistance and sensitivity to EGFR-based drugs in glioma.
Scintigraphic Evaluation of Local Recurrence of a Primitive Neuroectodermal Tumor
Authors: S S Sun, S C Tsai, N Y Hsu, C H Kao
Journal: Clinical Nuclear Medicine (2001)

SUN, SHUNG-SHUNG M.D.,*; TSAI, SHIH-CHUAN M.D.,†; HSU, NAN-YUNG M.D.‡; KAO, CHIA-HUNG M.D.* Author Information
Non-Hodgkin’s Lymphoma Causing a Symmetrical Renal Defect with the Rim Sign on Bone Scan
Authors: KEVIN K. L. CHOONG
Journal: Clinical Nuclear Medicine (2002)

From the Department of Nuclear Medicine and Ultrasound, Westmead Hospital, Westmead New South Wales, Australia Received for publication August 21, 2001. Revision accepted December 24, 2001. Correspondence: Kevin K. L. Choong, Department of Nuclear Medicine and Ultrasound, Westmead Hospital, Westmead, New South Wales 2145, Australia. E-mail: [email protected]
LIVING ALONE OR LIVING ONLY WITH AN ELDERLY SPOUSE IS AN INDEPENDENT PREDICTOR OF HOSPITAL READMISSION IN ELDERLY PATIENTS WITH DECOMPENSATED HEART FAILURE
Authors: Eisaku Nakane, Nozomi Tanaka, Yuki Kimura, Takayuki Sekihara, Hideyuki Hayashi, Mitsumasa Okano, Kanae Su, Masahiro Kimura, Moritoshi Funasako, Takao Kato, Shoichi Miyamoto, Toshiaki Izumi, Tetsuya Haruna, Moriaki Inoko
Journal: Journal of the American College of Cardiology (2015)
SP0168 The Synovium as a Stem Cell Niche for Joint Repair
Authors: C. De Bari
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> The synovium has remarkable self-renewal ability and self-regenerates in patients with inflammatory arthritis undergoing synovectomy. In addition, during osteoarthritis the joint demonstrates apparent repair mechanisms that can result in aberrant formation of cartilage and bone in the form of chondro-osteophytes. Altogether, this presumes existence of endogenous stem cells in the joint. More than a decade ago, we isolated from the adult human synovium mesenchymal stem cells (MSCs) with multipotency inherent at the single cell level (De Bari et al., Arthritis Rheum 2001). In a comparative study of MSCs from multiple tissue sources including bone marrow, the synovial MSCs displayed superiority in cartilage formation (Sakaguchi et al., Arthritis Rheum 2005), pointing to synovial MSCs as possible ideal chondroprogenitors for articular cartilage repair. We have postulated that postnatally the synovium may function as a reservoir of stem cells for the regeneration / repair of joint tissues such as articular cartilage and menisci that are known to have poor intrinsic regeneration potential. In this regard, the synovium shares with the joint surface a common embryonic derivation from the developmental joint interzone (Koyama et al., 2008; Rountree et al., 2004), while bone marrow and periosteum which, like synovium, contain MSCs in adult life, appear to have distinct developmental origins. In adult life, stem cells are considered as quiescent slow-cycling cells which, following injury, become activated and undergo proliferation and differentiation into mature cell type(s) in order to safeguard tissue anatomy and function. On the basis of this notion, we recently provided data on the identification and characterization of endogenous resident MSCs in the adult mouse knee joint synovium in vivo. We used a double nucleoside labelling scheme in a mouse model of knee joint surface injury (Eltawil et al., Osteoarthritis Cartilage 2009) and identified in the adult knee synovium long-term label-retaining slow-cycling cells that, following injury to the articular cartilage, proliferated and differentiated into chondrocytes, hence displaying typical features of adult stem cells (Kurth et al., Arthritis Rheum 2011). These slow-cycling cells were non-haematopoietic, non-endothelial stromal cells with a phenotype compatible with MSCs, and were located in the lining layer and in perivascular areas. Notably, these cells were distinct from pericytes. The existence of functional MSC niches in the adult joint opens up unprecedented opportunities for pharmacological interventions by using medications that would target MSC niches and related reparative signalling pathways to activate and modulate intrinsic joint tissue regeneration and, in a broader picture, to influence outcomes of joint disorders and restore joint homeostasis. <h3>Disclosure of Interest</h3> None Declared
Prostate Cancer Prevention Trial Launched
Authors: Tom Reynolds
Journal: JNCI Journal of the National Cancer Institute (1993)

Journal Article Prostate Cancer Prevention Trial Launched Get access Tom Reynolds Tom Reynolds Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 20, 20 October 1993, Pages 1633–1634, https://doi.org/10.1093/jnci/85.20.1633 Published: 20 October 1993
THU0472-HPR Calibration of a multidimensional item bank to measure fatigue in rheumatoid arthritis patients
Authors: S. Nikolaus, C. Bode, E. Taal, C. Glas, M. van de Laar
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Frequently used questionnaires to measure fatigue in rheumatoid arthritis (RA) are not developed from the patients’ perspective or have a fixed-length format. Modern psychometrics provide the possibility to measure patient reported outcomes precisely at individual level with few items. To be able to construct a computer adaptive test (CAT) that respectively selects items based on the previous answer of a patient, an item pool has to be constructed and calibrated according to item response theory (IRT). <h3>Objectives</h3> Goal of this study was the calibration of an item pool to measure fatigue in RA. It was based on the patients’ perspective captured by an interview study, and examined for face and content validity by a previous Delphi study with patients and professionals. The item pool contained 245 questions about fatigue. The fit of the items with the underlying dimensions was assessed with item response theory (IRT) and the dimensionality structure of the item pool was examined by factor analysis and multidimensional IRT. <h3>Methods</h3> Participants were 551 patients with RA from three hospitals in the Netherlands. Obviously, it was not feasible to let each patient score all 245 items of our item pool, so we used an item administration design to construct seven different questionnaire versions. Each patient completed one version of the questionnaire, maximally containing 126 items. IRT analysis using the generalized partial credit model (GPCM) was conducted for each dimension of fatigue. Poorly fitting items were removed. Consecutively, exploratory and confirmatory factor analysis was performed on the remaining items and a multidimensional IRT model was fitted. <h3>Results</h3> In the IRT analysis, 49 items showed insufficient item characteristics. Items with a discriminative ability &lt;0.60 and/or model misfit effect sizes &gt;0.10 were removed. Exploratory and confirmatory factor analysis on the 196 remaining items revealed three dimensions of fatigue named: severity, impact and variability of fatigue. The dimensions were further confirmed in multidimensional IRT model analysis. <h3>Conclusions</h3> This study provided an initially calibrated multidimensional item bank and has shown which dimensions and items that came forward from previous studies are important for the development of a multidimensional computerized adaptive test (CAT) for fatigue in RA. <h3>Disclosure of Interest</h3> None Declared
P373Two key regions of the human cardiac ryanodine receptor calcium release channel modulate its gating properties in a dual manner
Authors: C Viero, J Euden, SA Mason, MK Seidel, NL Thomas, S Zissimopoulos, AJ Williams
Journal: Cardiovascular Research (2014)

Ryanodine receptors type 2 (RyR2) regulate excitation-contraction coupling. Their dysfunction leads to pathological states, such as arrhythmia, heart failure and sudden death. Our homology model detected comparable structural determinants in the pores of the K+ channel KcsA and RyR2. A Glycine hinge motif in the inner transmembrane helix of many K+ channels is also found in RyR2. We tested the hypothesis that the Glycine at this position (4864) was critical for RyR2 function, as it is in K+ channels. A single substitution by Alanine in the human sequence did not alter Ca2+ release in transfected HEK293 cells, [3H]ryanodine binding or ion translocation and gating properties of purified channels, indicating that Glycine is not necessary. However Valine and Proline substitutions led to significant changes. Though well expressed in HEK293 cells, Valine mutant channels were not active as Ca2+ release entities in cells or as isolated channels reconstituted in planar lipid bilayers, and did not bind ryanodine (P<0.001 vs wild-type). The Proline mutation preserved the responses to caffeine and single channel activity, albeit with dramatic modifications, but [3H]ryanodine binding was abolished (P<0.01 vs wild-type). Our data suggest that a lack of flexibility in the pore impairs proper gating. To go further, we examined the NH2-terminal parts of RyR2 and showed by co-immunoprecipitation, chemical crosslinking and gel filtration that these domains can oligomerize within the tetrameric channel due to the presence of disulphide bonds. We used constructs (GST-BT4L) corresponding to the first 906 amino acids of the human RyR2 protein to test their interaction with endogenous NH2-terminal domains in HEK293 microsomes expressing RyR2. At diastolic Ca2+ concentrations (≤ 250 nM), GST-BT4L significantly induced a twofold increase in [3H]ryanodine binding (P<0.05 vs control). Moreover GST-BT4L raised the open probability of single channels (P<0.05 vs GST alone), in low Ca2+ conditions and with a physiological ion flow. Our results provide evidence that GST-BT4L can disrupt the NH2 terminus self-association, which moderately opens RyR2 channels. Hence, we propose that while a general flexibility of the pore inner helix is required to allow the channel to open, the tetramerization of the NH2 terminus domains facilitates RyR2 closure and prevents Ca2+ leak at diastolic Ca2+ concentrations. Since these two regions are hot spots of RyR2 mutations in Catecholaminergic Polymorphic Ventricular Tachycardia 1, these insights may have implications in the understanding of the mechanisms underlying this Ca2+ leak-related channelopathy.
EFFECTS OF A NOVEL TETRAPEPTIDE IN HEART FAILURE WITH REDUCED EJECTION FRACTION (HFREF): A PHASE I RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF ELAMIPRETIDE
Authors: Melissa A. Daubert, Eric Yow, Gary Dunn, Huiman Barnhart, Pamela Douglas, James Udelson, Christopher O’Connor, Sidney Goldstein, Hani Sabbah
Journal: Journal of the American College of Cardiology (2016)
Abstract 3596: Short-term effect of nose-only cigarette smoke exposure on redox homeostasis and mitochondrial metabolism in mice.
Authors: Haider Raza, Annie John, Abderrahim Nemmar
Journal: Cancer Research (2013)

Abstract The components of cigarette smoke have been implicated in the development of cancer as well as in cardiovascular diseases. We have previously reported oxidative stress in rat tissues induced by tobacco-specific toxins nicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Recently, we have also shown increased oxidative stress and associated inflammatory responses in various tissues after exposure to cigarette smoke. In this study, we have further investigated the effects of nose-only cigarette smoke exposure on mitochondrial functions and glutathione-dependent redox metabolism in tissues of BALB/C mice. Liver, kidney, heart and lung tissues were analyzed for oxidative stress, glutathione (GSH) and cytochrome P450 dependent enzyme activities and mitochondrial functions after exposure to smoke generated by 9 cigarettes/day for 4 days. Control mice were exposed to air only. An increase in oxidative stress as observed by an increased production of reactive oxygen species (ROS) and altered GSH metabolism was apparent in all the tissues, but lung and heart appeared to be the main targets affected. Increased expression and activity of CYP450 1A1 and 1A2 were also observed in the tissues after exposure to cigarette smoke. Mitochondrial respiratory functions in the tissues, as observed by alterations in the activities of Complex I and IV enzymes, was also observed after exposure to cigarette smoke when compared with air only exposed mice. SDS-PAGE and Western blot results also indicate that alterations in the expression of enzyme proteins were in accordance with the changes in their catalytic functions. These results suggest that even short term exposure of cigarette smoke have adverse effects on mitochondrial functions and redox homeostasis in tissues which may progress to further complications associated with chronic smoking. (The study is supported by Terry Fox Cancer Research Funds and by the Research Committee Grants from College of Medicine and Health Sciences) Citation Format: Haider Raza, Annie John, Abderrahim Nemmar. Short-term effect of nose-only cigarette smoke exposure on redox homeostasis and mitochondrial metabolism in mice. [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 3596. doi:10.1158/1538-7445.AM2013-3596
BMI-DEPENDENT EFFECTS OF ADIPOSE TISSUE EXOSOMES ON HUMAN MACROPHAGE CHOLESTEROL TRANSPORT GENE EXPRESSION
Authors: Allison B. Reiss, Joshua DeLeon, Iryna Voloshyna, Sarah Ferrante, Nicolle Siegart, Ashley Barlev, Michael Littlefield, Michael Salama, Lora J. Kasselman, Robert J. Freishtat
Journal: Journal of the American College of Cardiology (2016)
O5.01 * STANDARDS AND ADVANCED TESTING FOR INTRAOPERATIVE LANGUAGE AND COGNITIVE MAPPING
Authors: A. Comi, M. Riva, A. Casarotti, E. Fava, F. Pessina, C. Papagno, L. Bello
Journal: Neuro-Oncology (2014)

Resection of tumors involving language pathways requires the intraoperative identification of cortical and subcortical sites mediating the various language components, which determines the extent of resection (EOR). One of the critical point is which test(s) has to be performed during subcortical mapping. Object naming is the most used one, but it may have the limit to miss other components of language such as verb naming and generation, or comprehension of words or sentences, potentially resulting in permanent post operative deficits. Patients can be submitted intraoperatively to complex batteries of tests, resulting in limited performance and high chance of intraoperative fatigue, resulting in poor mapping. We revised our experience on subcortical language mapping in a series of patients with language pathways gliomas, in which two strategies for subcortical mapping were applied: in a first group only naming was used; in the second group, object naming was prevalently used but integrated with other tests (verb naming and generation, comprehension of words or sentences, number recognition and calculation). Results were evaluated as immediate and permanent deficits by applying a large neuropsychological testing, and as EOR (on volumetric FLAIR or post Gd T1 images). The first group was composed of 221 gliomas (168 LGGs, 53 HGGs); 130 were frontal, 21 in the insula, 58 temporal, and 12 parietal. Object naming was applied for subcortical mapping in all cases; 198 patients had immediate post operative deficits. Neuropsychological evaluation at 1 months showed complete recovery in 199 patients, a mild impairment was documented in 22 patients (12 posterior temporal tumors, 6 parietal tumors, and 4 posterior insular tumors); at 3 months evaluation, 15 patients still showed a mild impairment, mainly those whose tumors were located in the posterior temporal and parietal location. EOR was total and subtotal in 48.9% and 41.5% of cases. Fatigue was observed in 12% of patients with large volume tumors. The second group was composed of 179 gliomas (155 LGGs, 24 HGGs); 61 were frontal, 38 insular, 45 temporal and 11 parietal. Object naming was used for initial mapping and for locating main subcortical tracts (IFOF, ARC, UNC); in addition, when the initial portion of these tracts was identified, other tests were applied during subcortical mapping. 165 patients had immediate post operative deficits, only 2 patients had a mild impairment at 1 and 3 months evaluation. EOR was total and subtotal in 49.6% and 47.4% of cases. Patient fatigue was shown in 9% of patients. Object naming can be safely used during subcortical mapping for resection of tumors in frontal lobe; resection of tumors in posterior temporal, insular and parietal areas requires the use of a larger battery of tests, which did not influence the chance to reach a total or subtotal resection, nor results in a higher chance of patient fatigue.
LEFT ATRIAL APPENDAGE CLOSURE DURING ROUTINE CARDIAC SURGERY INCREASES THE RISK OF POSTOPERATIVE ATRIAL FIBRILLATION AND DOES NOT REDUCE THE RISK OF STROKE: A PROPENSITY SCORE MATCHED ANALYSIS OF 9,833 PATIENTS
Authors: Rowlens Melduni, Eloka Ikebudu, Rakesh Suri, Hon-Chi Lee, Stephen Cha, Samuel Asirvatham, Hartzell Schaff, James Seward, Bernard Gersh
Journal: Journal of the American College of Cardiology (2015)
Heart or Head?
Authors: William A. Gray, Douglas M. Barrett, J. William Benge
Journal: New England Journal of Medicine (1999)

A 65-year-old woman was referred to a cardiologist for the evaluation of progressive chest pain. Placement of an aortobifemoral conduit had been performed 14 years earlier for occlusive aortoiliac disease. She had smoked two packs of cigarettes a day for over 40 years. Her history of chest pain was typical of crescendo angina pectoris on exertion, without symptoms that were prolonged or that occurred at rest. Two years earlier, she had had a transient ischemic attack consisting of facial droop and aphasia. She had bilateral carotid bruits, which were greater on the left side than on the right, and . . .
THU0086 Adherence to Therapy and Treatment Outcomes in Patients with the Different Ways of Spondyloarthritis Monitoring
Authors: I. Gaydukova, A. Rebrov, A. Akulova, A. Aparkina
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Monitoring is an important part of the disease management in patients with axial spondyloarthritis (axSpA) [1]. <h3>Objectives</h3> is to evaluate the differences in adherence to therapy and in treatment outcomes in patients with the different ways of SpA monitoring. <h3>Methods</h3> A total of 168 TNFα-blockers naïve patients with axial SpA fulfilling the ASAS criteria with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 were involved in the current study and followed-up for one year. Ninety six patients were managed in by a local rheumatologist, who determined the frequency of monitoring and treatment required (group 1); 26 patients were managed actively – they visited rheumatologist every 12 weeks (group 2); 46 patients were involved in the group of the remote telephone monitoring – a monitor called them every 4 weeks and collected data about treatment and disease activity (group 3). Data on treatment and disease activity (BASDAI, the Ankylosing Spondylitis Disease Activity Score – ASDAS, and the patient acceptable symptom state – PASS) were collected at baseline and after 1 year of follow-up. Patients were asked if they need a rheumatologist9s consultation. <h3>Results</h3> In group 1 BASDAI at baseline was 5.32±3.2, after one year – 5.17±2.16, ASDAS – 3.45±2.1 and 3.1±1.1, respectively (p&gt;0.05). In group 2 BASDAI at baseline was 5.21±3.0, after 1 year – 4.77±2.2, p&lt;0.05, ASDAS – 3.42±2.9 and 2.79±2.6, respectively, p&lt;0.05. In group 3 (remote monitoring) BASDAI at baseline was 5.36±3.5, after one year – 3.17±2.12, p&lt;0.05, ASDAS – 3.44±3.1 and 2.6±1.8, respectively, p&lt;0.05. Positive PASS at one year was achieved in the group 3 in 15 (57.69%, n=26), in group 2 - in 4 (20%, n=20), and in group 1 – in 0 (0%) of the cases. During one year non-steroid anti-inflammatory drugs intake recommended at baseline was changed arbitrarily (canceling the treatment/reducing the dose of medication) by 5 (19.23%, n=26), 15 (75%, n=20), 93 (96.87%, n=96) patients in groups 3, 2 and 1, respectively. After one year of follow up 3 patients of group 3 (11.5%, n=26), 19 (95%, n=20) of group 2 and 96 (100%) patients of group 1 considered that they need to visit a rheumatologist. <h3>Conclusions</h3> Regular monitoring is associated with a better therapy outcome in axSpA. Remote telephone monitoring of SpA every 4 weeks seems to beneficial regarding better adherence to therapy and better treatment outcomes than active monitoring of the disease every 12 weeks or irregular monitoring. <h3>References</h3> Braun J. Ann Rheum Dis. 2011; 70: 896–904. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3960
Recanalization using diathermic dilator for stent obstruction due to tumor ingrowth
Authors: Takeshi Ogura, Daisuke Masuda, Akira Imoto, Rieko Kamiyama, Saori Onda, Kazuhide Higuchi
Journal: Endoscopy (2014)

Endoscopic biliary drainage has become established as first-line treatment for obstructive jaundice. However, if the stent becomes obstructed by tumor ingrowth, re-intervention can sometimes be challenging. One of the challenges can be difficulty in dilating the stricture. Several techniques for resolving this have been reported, such as those using the Soehendra stent retriever or a needle-knife catheter [1] [2]. More recently, Kawakami et al. have reported on the clinical impact of transpapillary dilation of refractory severe biliary stricture and main pancreatic duct stricture using a diathermic dilator (Cysto-Gastro-Set; Endo-Flex GmbH, Voerde, Germany) ([Fig. 1]) [3] [4]. We report successful treatment for stent obstruction due to tumor ingrowth using this diathermic dilator.