tbuckley/cabot-search huggingface dataset:
Abstract 4395: Functional domains in glyceraldehyde-3-phosphate dehydrogenase modulating its enzymatic activity and intracellular localization
Authors: Manali S. Phadke, Anurag Mishra, Natalia Krynetkaia, Evgeny Krynetskiy
Journal: Cancer Research (2011)

Abstract Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that plays a pivotal role in energy homeostasis of cancer cells. In response to several types of stress including genotoxic stress, GAPDH accumulates in the nucleus; its intranuclear functions remain to be elucidated. Earlier we demonstrated that, following genotoxic stress and intranuclear translocation in human lung carcinoma cells, GAPDH binds yet to be identified nuclear components. Using site mutagenesis, we prepared several mutated variants of GAPDH containing T99I and K259N amino acid substitutions, or a stop codon at position 263. Wild type GAPDH and mutated variants were expressed in BL21(DE3) bacterial system and purified by Ni-chromatography. Catalytic properties of the mutant proteins were compared with the wild type GAPDH. Catalytic activity of GAPDH protein was significantly reduced in the T99I mutant variant (Vmax 1.6±0.33 U/mg vs Vmax 40±1.9 U/mg of wild type GAPDH), while there was no significant difference in Vmax between the K259N variant and wild type GAPDH (p = 0.97). Truncated GAPDH (K263STOP) did not reveal any detectable catalytic activity. To assess the effects of mutations on intracellular localization of GAPDH, we prepared synthetic constructs coding for GFP-fusion variants of GAPDH (T99I, K259N, K263STOP) and used them for transient transfection of isogenic human carcinoma cell lines HCT116 (40-16; p53+/+ and 379.2; p53-/-) and SW48 (297; p53+/+ and 213; p53-/-). Intracellular distribution of wild type and mutant GAPDH was assessed by confocal microscopy and image analysis. Consistent with previous findings, wild-type GAPDH was excluded from the nucleus in the absence of stress, and accumulated in the nucleus following treatment with genotoxic agent cytarabine. In contrast, both T99I and K259N mutations significantly increased intranuclear content of GAPDH before and after stress. Truncated variant GAPDH (1-262) was evenly distributed in cytosolic and nuclear compartments. No significant difference was found in GAPDH localization between p53-proficient and p53-deficient isogenic cell lines indicating that p53 does not mediate GAPDH intranuclear localization. Our results identify the important functional domains of GAPDH that determine GAPDH intracellular localization. These domains are involved in interactions with intranuclear components of the cells experiencing genotoxic stress. * both have contributed equally to this work This work was partially supported by NCI grant R01 CA104729 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 4395. doi:10.1158/1538-7445.AM2011-4395
Abstract 2479: Detecting Abelson tyrosine kinase activation by ATM and DNA-PK after exposure to ionizing radiation using a peptide biosensor
Authors: Jiabin Tang, Jean Y. Wang, Laurie Parker
Journal: Cancer Research (2011)

Abstract Abelson (Abl) kinase is a non-receptor tyrosine kinase that is involved in many cellular processes, including survival, differentiation and apoptosis. Abl is activated in the response to DNA damage, and is involved in the decision between DNA repair versus apoptosis. It is widely accepted that Abl is regulated in response to DNA double-strand breaks (DSBs) by ataxia telangiectasia mutated protein (ATM) via phosphorylation of Abl at S465. However, other aspects of this complex signaling response have been unclear, including the role of other kinases such as DNA-dependent protein kinase (DNA-PK), because of the difficulties of detecting subtle changes in Abl activation through endogenous substrates. Here, we show Abl is activated in a mutant cell line that cannot be phosphorylated by ATM at S465 (Abl-S465A-EGFP) after exposure to ionizing radiation (IR) using a peptide biosensor we developed for Abl kinase. This biosensor contains the following functional modules: a highly specific Abl kinase substrate, an Abl SH3 binding ligand, a photocleavable linker, a biotin tag and a cell penetrating peptide derived from Hiv-TAT to aid intracellular delivery of cargo across the plasma membrane. Using a combination of chemical biology approaches, Western blot for the phosphorylation of the biosensor peptide and high-resolution MS-based phosphoproteomics, we identified a potential role for DNA-PK in activating Abl kinase after IR, independent of ATM and S465. This information about the importance of DNA-PK in this signaling pathway may lead to a better understanding of c-Abl's function in the response to IR, and could be useful to develop strategies to combat radioresistance or improve radiosensitivity in tumors. 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 2479. doi:10.1158/1538-7445.AM2011-2479
Tc-99m Sestamibi Scintimammography in the Evaluation of Response of Breast Carcinoma to Chemotherapy
Authors: A I Joaquim, A J Sagarra, C D Ramos, R Coudry, R A Sagarra, E E Camargo
Journal: Clinical Nuclear Medicine (1997)

A 44-year-old premenopausal woman had a T3N0M0 breast cancer in the inner superior quadrant of the left breast. Her biopsy revealed a histologic grade III and nuclear grade II invasive ductal carcinoma with foci of comedocarcinoma. The patient was placed on three cycles of neoadjuvant chemotherapy with cyclophosphamide, epirubicin, and fluorouracil (FEC). Scintimammography, mammography, and histopathologic evaluation were obtained prior to and after treatment to evaluate the tumor response to chemotherapy. After modified radical mastectomy, histopathology demonstrated only 10% of viable tumor cells, 80% of collagenization, and 10% of tumor necrosis.
Striking junior doctors will return to work in emergency, says BMA
Authors: Abi Rimmer
Journal: BMJ (2016)

Junior doctors taking full strike action would return to work in the case of a national emergency, the chair of the BMA Junior Doctors Committee has said.

The association announced on 23 March that industrial action by junior doctors scheduled for 26 April would change from 48 hour emergency care only to a full withdrawal of labour.1 It said that junior doctors would withdraw all labour from 8 am to 5 pm on Tuesday 26 and Wednesday 27 April.

Commenting on the action, Johann Malawana, chair of the BMA Junior Doctors Committee, …
FOXO3A DEFICIENCY PROTECTS FROM COXSACKIEVIRUS B3 MYOCARDITIS: ROLE OF NK CELL FUNCTION
Authors: Luise Holzhauser, Madlen Löbel, Alexander Jenke, Moritz Becher, Sandra Bauer, Sandra Pinkert, Henry Fechner, Wolfgang Poller, Heinz-Peter Schultheiss, Carmen Scheibenbogen, Carsten Skurk
Journal: Journal of the American College of Cardiology (2015)
Global health leader was among six AIDS experts killed travelling to conference
Authors: B. Roehr
Journal: BMJ (2014)

Six people travelling from Amsterdam to the 20th International AIDS Conference in Melbourne, Australia, were among the 298 people who died when Malaysia Airlines flight 17 crashed in Ukraine.

The conference opened on the evening of 20 July, with many attendees acknowledging their colleagues’ contributions and passing. Ironically, the opening plenary address of the conference was named in honour of Jonathan Mann, a former director of the World Health Organization’s global AIDS programme. He and his wife, Mary Lou Clements-Mann, who was an HIV researcher at the Johns Hopkins Bloomberg School of Public Health, had died …
Arsenic: the largest mass poisoning of a population in history
Authors: Parijat Sen, Tamoghna Biswas
Journal: BMJ (2013)

Millions of Indians are exposed to natural arsenic contamination in drinking water, leading to an array of health problems. But is the government doing enough, ask <b>Parijat Sen</b> and <b>Tamoghna Biswas</b>
Emerging cephalosporin and multidrug-resistant gonorrhoea in Europe
Authors: M J Cole, G Spiteri, S A Chisholm, S Hoffmann, C A Ison, M Unemo, M Van de Laar
Journal: Eurosurveillance (2014)

Neisseria gonorrhoeae has consistently developed resistance to antimicrobials used therapeutically for gonorrhoea and few antimicrobials remain for effective empiric first-line therapy. Since 2009 the European gonococcal antimicrobial surveillance programme (Euro-GASP) has been running as a sentinel surveillance system across Member States of the European Union (EU) and European Economic Area (EEA) to monitor antimicrobial susceptibility in N. gonorrhoeae. During 2011, N. gonorrhoeae isolates were collected from 21 participating countries, and 7.6% and 0.5% of the examined gonococcal isolates had in vitro resistance to cefixime and ceftriaxone, respectively. The rate of ciprofloxacin and azithromycin resistance was 48.7% and 5.3%, respectively. Two (0.1%) isolates displayed high-level resistance to azithromycin, i.e. a minimum inhibitory concentration (MIC) ≥256 mg/L. The current report further highlights the public health need to implement the European response plan, including further strengthening of Euro-GASP, to control and manage the threat of multidrug resistant N. gonorrhoeae.
Withdrawal of Digoxin from Patients with Chronic Heart Failure Treated with Angiotensin-Converting-Enzyme Inhibitors
Authors: Milton Packer, Mihai Gheorghiade, James B. Young, Peter J. Costantini, Kirkwood F. Adams, Robert J. Cody, L. Kent Smith, Lucy Van Voorhees, Lynn A. Gourley, M. King Jolly
Journal: New England Journal of Medicine (1993)

Although digoxin is effective in the treatment of patients with chronic heart failure who are receiving diuretic agents, it is not clear whether the drug has a role when patients are receiving angiotensin-converting-enzyme inhibitors, as is often the case in current practice.
First cancer patient has new metabolic imaging technique in UK trial
Authors: Susan Mayor
Journal: BMJ (2016)

A patient with cancer has become the first in Europe to undergo scanning with a new metabolic imaging technique, in a UK trial designed to assess whether it can rapidly detect a drug treatment’s effectiveness at killing cancer cells.

The imaging technique uses hyperpolarised pyruvate, a breakdown product of glucose that is labelled with non-radioactive carbon-13 ([1-13C] pyruvate), to characterise alterations in tumour metabolism non-invasively. …
Abstract 292: Breast cancer malignancy is regulated by PAX5 through the disruption of FAK1 signaling.
Authors: Sami Benzina, Pierre O'Brien, Roxann Guerrette, Gilles Robichaud
Journal: Cancer Research (2013)

Abstract Breast cancer is the most common cancer diagnosed in women worldwide. 30% of these women will succumb to their disease. More specifically, metastasis accounts for 90% of deaths in breast cancers patients. Therefore, the study of genetic factors regulating cancer malignancy is a top priority to mitigate the morbidity and mortality associated to this disease. PAX5 (Paired Box 5) is a transcriptional factor normally implicated in embryogenesis and B cell differentiation. However, the aberrant expression of PAX5 is associated to several types of cancer pathology and more recently in breast cancer. We have recently reported that PAX5 promotes epithelialisation and its expression inversely correlates with the Focal Adhesion Kinase 1 (FAK1), a key component in cancer motility and invasion leading to metastasis. On one hand, these finding suggest that PAX5 could attenuate FAK-mediated epithelial-mesenchymal transitioning (EMT) of primary tumors. On the other hand, PAX5 could also initiate the mesenchymal-epithelial transitioning (MET) of circulating cancer cells enabling them to colonize and establish secondary tumours. In this study we set out to validate the role of PAX5 in the metastatic cascade of mammary tumours, particularly to uncover the molecular regulation of FAK1 cascades through PAX5 in breast cancer cell malignancy. Through conditional expression of the PAX5 gene in breast cancer cells, we demonstrate experimentally a negative regulation of FAK1 protein and phosphorylation levels mediated by PAX5 over expression. We also confirm that PAX5 suppresses the transcriptional expression of FAK1. Further investigation shows a PAX5-mediated suppression of FAK1 signaling pathways (e.i. AKT, p38, JNK and Paxillin) leading to attenuated cancer cell proliferation, death and migration processes. These findings bring light to molecular mechanisms driving breast cancer malignancy and benefit our quest in the development of diagnostic and therapeutic strategies. Citation Format: Sami Benzina, Pierre O'Brien, Roxann Guerrette, Gilles Robichaud. Breast cancer malignancy is regulated by PAX5 through the disruption of FAK1 signaling. [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 292. doi:10.1158/1538-7445.AM2013-292
AB1112 Ten years of etanercept therapy for juvenile idiopathic arthritis in vienna
Authors: A. Ulbrich, J. Hruby, S. Rippel, H. Schacherl, C. Schreiner, G. Artacker, W. Emminger
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Eighty-eight patients suffering from juvenile idiopathic arthritis (JIA) with inadequate response to methotrexate therapy (MTX) have received etanercept +/- MTX since the year 2000 in Vienna. They were retrospectively analysed. They were suffering from various categories of JIA (systemic JIA, persistent or extended oligoarthritis, seronegative or seropositive polyarthritis or from psoriatic arthritis). The data were collected in three pediatric outpatient units. <h3>Results</h3> The mean age at diagnosis was 8,1±4,5 years (from 8,9 months to 16,2 years), there were 25 boys (28,4%) and 63 girls (71,6%) (ratio 1: 2,5). The mean period of time from diagnosis until the onset of a therapy with methotrexate (MTX) was 1,6 years (sd ± 2,1, from 0,8 months to 11,1 years). All patients were treated with MTX for 3,1 years (sd ± 2,8, from 3,0 months to 12,8 years). Currently 27 patients are still treated with MTX. The mean period of time from diagnosis to etanercept therapy was 4,5 years (sd ± 3,5, from 4,0 months to 15,0 years). Patients were treated with Etanercept for 1,7 years (sd ± 1,0, from 1,0 months to 4,1 years). In september 2011, there were still 62 patients (70,5%) treated with Etanercept. 20 patients (32,3%) are in remission, 16 (25,8%) have active arthritis, 3 (4,8%) have at least one tender joint (POM = pain of motion), 16 (25,8%) have at least one limited joint (LOM = limitation of motion) and 7 (11,3%) could not be evaluated. At the time of diagnosis there were 1 – 38 joints (mean 12,7) affected, at the time of onset of the MTX therapy there were 1 – 38 joints (mean 8,3) affected. In september 2011, there is a significant decrease in the number of affected joints (0 – 22 joints; mean 3,0; p&lt;0,05). <h3>Conclusions</h3> Our data show that the patients showed a remission after an average of 6,1 months (sd ± 7,1; 0,7 months – 2,8 years). 33 (37,5%) of these patients are stilll in remission (16 on therapy with etanercept, 4 on therapy with etanercept + MTX, one on therapy with MTX and 12 are off therapy) and this status persists for 2,4±1,2 years after withdrawal of etanercept. <h3>Disclosure of Interest</h3> None Declared
O1.07 * INTRACRANIAL HEMANGIOPERICYTOMAS LACK TYPICAL CYTOGENETIC AND EPIGENETIC FEATURES OF MENINGIOMAS: A COMPREHENSIVE MOLECULAR GENETIC STUDY
Authors: D. Kraemer, S. I. Orie, R. Ketter, J. Oertel, S. Urbschat
Journal: Neuro-Oncology (2014)

OBJECTIVE: Cranial hemangiopericytomas are rare tumors of mesenchymal origin with a high proclivity towards recurrence and extraneural metastasis. Considering the paucity of reports dealing with the tumor genetics of cranial hemangiopericytomas and the still ongoing debate about their histological standing, we examined a series of 9 cranial hemangiopericytomas for the most important meningioma specific cytogenetic and epi-genetic aberrations. Furthermore, for the first time, whole genomic imbalances were assessed by chromosomal CGH analysis. MATERIAL AND METHODS: In a total of nine histopathologically confirmed CNS-hemangio-pericytomas, the promoter methylation status of p15(CDKN2B), p16INK4A, TIMP3, MGMT and NDRG2 genes were evaluated via MS-PCR and direct bisulfite sequencing, respectively. Furthermore, typical numerical chromosomal aberrations reported in meningiomas were investigated using two-color FISH on touch-preparations with locus specific probe pairs detecting 1p36/22q11, 14q24/18q21, and 9p21/10q23 (MetaSystems, Altlußheim, Germany). For CGH analysis, standard procedures were used. RESULTS: All studied cases presented with an unmethylated status of the p15,MGMT and TIMP3 promoters. One specimen was encountered with positive methylation signal for p16 in MS-PCR analysis. Direct bisulfite sequencing for NDRG2 revealed only in 1/6 cases a moderately elevated average methylation degree. In FISH analyses, disomy for all targeted chromosomal regions was found in 5/9 studied hemangiopericytoma specimens; in two tumors a slight clone with hemizygous loss of 10q23 was detected. In one other specimen, virtually all nuclei harbored a hemizygous deletion of 9p21. One further CNS-hemangiopericytoma was characterized by a tetraploid mainline with slight sidelines that contained trisomies of 9p21 and 10q23. CGH analysis revealed heterogeneous copy number changes for each of the nine hemangiopericytomas (8.2 alterations on average), involving all chromosomes besides chromosomes 14, 15, and 21. Most frequently, chromosomes 4 and 18 were affected by DNA changes. On subchromosomal level, most recurrent aberrations involved the exclusive gains on 7q11.2, 16p13.2 ∼ p13.3, and 18p11.3 as well as the exclusive segmental loss of 20q13.2 ∼ q13.3. CONCLUSIONs: Most CNS-hemangiopericytomas obviously lack meningioma specific epigenetic and molecular cytogenetic lesions, further providing evidence that they represent a distinct tumor entity with genetic different features. The present findings prompt one to speculate about the possible role of inactivation of p16INK4a and deletions on 10q in the underlying tumorigenesis of a distinct subgroup of CNS-hemangiopericytomas. By use of CGH analysis, novel regions of gains and losses were identified which will help to further elucidate potentially causal genetic events for genesis of cranial hemangiopericytomas.
P16.25 * THE ROLE OF PET F-FDOPA IN THE EVALUATION OF GLIOMAS
Authors: A. Pace, V. Villani, A. Vidiri, A. Chiaravalloti, R. Floris, O. Schillaci, A. Fabi, I. Terrenato, F. Piludu, C. M. Carapella
Journal: Neuro-Oncology (2014)

BACKGROUND: Brain Tumours (BTs) have been widely evaluated using the 3,4-dihydroxy-6-18 fluoro-L-phenylalanine (F-18-FDOPA) PET. The aim of the study was to evaluate the role of PET FDOPA in low grade glioma (LGG). METHODS: We enrolled all patient affected by LGG. All patients underwent FDOPA PET and MRI examination. METHODS: Both FLAIR and contrast-enhanced T1-weighted sequences were considered for the response assessment to treatment in according to RANO criteria. The PET images were interpreted as positive when the lesion definitely increased F-FDOPA accumulation taking into consideration the background and the controlateral site. The slices with a maximal F-FDOPA uptake in the ROI were chosen for quantitative measurement of metabolic activity of the tracer [standardized uptake value (SUV)]. In order to evaluate the concordance between diagnostic test 1 (MRI) and diagnostic test 2 (FDOPA) we calculated the unweighted kappa statistic and its relative 95% Confidence interval (95%CI). This value was interpreted in a qualitative manner on the basis of the Landis and Koch classification criteria. RESULTS: We enrolled 56 (35 males and 21 females) patients affected by LGG. The mean age at diagnosis was 44.5 years. Out of the 56 patients recruited for this study, 23% were a newly diagnosed, 45% in chemotherapy treatment, and 32% were untreated but had a regular follow-up. The Kappa statistic for the whole sample was equal to 0.301 (95%CIs from 0.21 to 0.40) showing a fair concordance between the two tests in terms of diagnostic capability. We found a good correlations between residual volume and SUV max (r = 0.435, p = 0.002 by Spearman Rank Correlation Coefficient), indicating that the greater the residual volume, the higher the SUV max was. Also the multivariate analysis showed that a SUV max greater than 1.65 was the only independent predictor of disease progression (HR = 4.59, 95% CIs from 0.99 to 21.31, p = 0.054). This implies that a patient with a SUV max higher than 1.65 had an almost 5-fold increased risk of disease progression, regardless of its clinical and MRI characteristics. CONCLUSION: Our results confirm that PET 18F-FDOPA may be a role diagnostic and prognostic in patients with LGG.
AB0484 Levels of C-Peptide in Lupus Erythematosus Patients after Glucocorticoid Pulse-Therapy in Short Term Period
Authors: G. Nurullina, F. Valeeva
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> C-peptide reflects the level of endogenous insulin secretion and enables the evaluation of pancreatic β-cell function. <h3>Objectives</h3> To evaluate the influence of glucocorticoid pulse-therapy (GT PT) on the level of plasma C-peptide in patients with lupus erythematosus (LE) after the infusion in short-term. <h3>Methods</h3> The study included 20 patients (men – 2, women - 18) with LE aged 18-61 years (mean age 37,56±13,02) and duration of disease 1 to 12 years (mean 3,92±3,81). GC PT consisted of intravenous infusion of 600-1000 mg of prednisone a day with 250 ml of 0,9% isotonic solution for 3 consecutive days (1 course of 3 infusions). Total dose for a course was 1800-3000 mg/day. For the evaluation of C-peptide plasma levels we used enzyme-linked immunosorbent assay (ELISA) for the evaluation of C-peptide proinsulin in human blood and plasma. Reference range: 0,9 – 4,0 ng/ml. We performed the evaluation of glucose levels in all patients before the start of PT and at 2, 4, 6,10, 24, 48 and 72 hours after the infusion, and in patients with abnormal blood glucose level at 72 hours after the infusion the evaluation was continued until normalization of blood glucose levels. The evaluation of C-peptide level was performed before the start of PT infusion and at the climax of glycemia. <h3>Results</h3> Mean C-peptide level before the start of GC PT was 1,9±1,35 mmol/l (0,55 to 4,0 ng/ml) All patients demonstrated an increase of blood glucose levels after the course of GC PT, reaching maximum 4 hours after the start of the infusion - 12,1±3,26 ng/ml (7,3 to 22,2 ng/ml). At the peak glycemia after GC PT the level of C-peptide was 8,84±4,19 ng/ml (2,56 to 16,11 ng/ml), demonstrating a 4,7-fold increase of C-peptide level. <h3>Conclusions</h3> GC PT in LE patients is associated with an elevation of blood glucose an C-peptide levels reaching peak values at 4 hours after the start of the infusion and remaining elevated for 2 or more days. The increase of C-peptide level reflects the increase of endogenous insulin production, which accompanies the increase of blood glucose level, pointing to possible insulin resistance, which can be a predictor of profound carbohydrate metabolism disturbance. Our data substantiate the need to perform additional blood glucose evaluation in this group of patients. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4328
HOMING PATTERN OF INDIUM-111 PERIPHERAL BLOOD MONOCYTES IN RATS.
Authors: L. P. Kasi, G. Lopez-Berestein, K. Gray, R. Halpern, J. Turpin, H. J. Glenn, T. P. Haynie
Journal: Clinical Nuclear Medicine (1984)

Kasi, L. P.; Lopez-Berestein, G.; Gray, K.; Halpern, R.; Turpin, J.; Glenn, H. J.; Haynie, T. P. Author Information