tbuckley/cabot-search huggingface dataset:
Abstract 1947: FAM129B regulates cell proliferation and activates NF-κB and Nrf2 by inactivating KEAP1 in cancer cells
Authors: You-Chin Lin, Kai-Chung Cheng, Alan Chuan-Ying Lai, Yu-Ju Chen, Alice L. Yu
Journal: Cancer Research (2011)

Abstract The Family with sequence similarity 129 (FAM129) contains three membrane proteins, FAM129A, B and C. FAM129A (also called Niban) and FAM129C (also called BCNP1) have been found to be up-regulated in thyroid tumors and chronic lymphocytic leukemia, respectively. Although phosphorylation of FAM129B has been suggested to play a role in controlling melanoma cell invasion, the molecular mechanism of FAM129B in tumorigenesis remains largely unknown. In this study, we first identified FAM129B as one of proteins with altered phosphorylation status in breast cancer stem cells by the phosphor-mass spectrum technique. Silencing of FAM129B expression in breast cancer cell line, MDA-MB-231, led to decreased proliferation, along with flattened and rounded cell morphology. By mammalian two-hybrid system and FRET (fluorescence resonance energy transfer) assay, KEAP1 (kelch-like ECH-associated protein 1) was detected to interact with FAM129B. KEAP1 has been reported to function as a substrate adaptor protein for Cul3-dependent E3 ligase complex to repress IKKβ and transcription factor Nrf2. We indeed observed that the expression of NF-κB and Nrf2 downstream genes, FN1 and NQO1, was down-regulated in FAM129B-silenced cells by qPCR analysis. On the other hand, FAM129B together with either IKKβ or Nrf2 synergistically activated NF-κB and Nrf2 promoter activity by reporter assays. Taken together, our results suggest that FAM129B might play an important role in the regulation of cell proliferation in cancers by inactivating KEAP1 which in turn activates Nrf2 and IKKβ activities. 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 1947. doi:10.1158/1538-7445.AM2011-1947
Comparison of Carbamazepine, Phenobarbital, Phenytoin, and Primidone in Partial and Secondarily Generalized Tonic–Clonic Seizures
Authors: Richard H. Mattson, Joyce A. Cramer, Joseph F. Collins, Dennis B. Smith, Antonio V. Delgado-Escueta, Thomas R. Browne, Peter D. Williamson, David M. Treiman, James O. McNamara, Charlotte B. McCutchen, Richard W. Homan, Wayne E. Crill, Michael F. Lubozynski, N. Paul Rosenthal, Assa Mayersdorf
Journal: New England Journal of Medicine (1985)

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.
Additional Benefit of F-18 FDG PET/CT in the Staging and Follow-up of Pediatric Rhabdomyosarcoma
Authors: Fabien Ricard, Sébastien Cimarelli, Emmanuel Deshayes, Thomas Mognetti, Philippe Thiesse, Francesco Giammarile
Journal: Clinical Nuclear Medicine (2011)

The therapeutic management of rhabdomyosarcoma (RMS) is strongly dependent on initial staging. This study aimed to evaluate F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) as an adjunct to conventional imaging (CI) in the staging and follow-up of pediatric RMS.A total of 13 consecutive children and adolescents (12 males, 1 female; mean age, 9.6 years) with histologically proven RMS (10 alveolar, 3 embryonal), in whom FDG PET/CT was performed at staging and follow-up, were retrospectively included. In total, 35 FDG PET/CT were compared with CI (MRI, CT, and bone scintigraphy) performed with a less than a 15-day interval. Histologic data, follow-up (mean, 27 months), and the final judgment of a multidisciplinary tumor board were considered as the standard of reference for result interpretation.At staging, FDG PET/CT revealed 1 RMS of the prostate missed by CI, and found 19 true-positive lymph node territories in 4 patients and 11 bone metastases in 3 patients, versus 12 and 3, respectively, with CI. Conversely, FDG PET/CT was less sensitive for detecting infracentimetric lung nodules in 1 patient. On the whole analysis, FDG PET/CT modified lymph node staging in 4 of 13 patients, bone involvement in 2 patients, and led to treatment alteration in 2 children.FDG PET/CT can be useful in staging and restaging pediatric RMS, especially for assessing lymph nodes and bone involvement, and for detecting unknown primary sites of RMS, with potential therapeutic strategy alteration.
Abstract 2009: A new repressive network module in Ewing's Sarcoma
Authors: Maximilian O. Kauer, Gunhild Jug, Stephan Niedan, Robert L. Walker, Paul S. Meltzer, Heinrich Kovar
Journal: Cancer Research (2010)

Abstract The EWS-FLI1 chimeric transcription factor characteristic of Ewing's sarcoma family tumors (ESFT) constitutes the prototype of an aberrant ETS transcription factor causally involved in oncogenesis. However, the mechanisms of transcriptional regulation leading to ETS driven tumorigensis are poorly understood. Previously, we have successfully established and tested a research plan that proceeds from genomics data production, via bioinformatic generation of specific hypotheses to functional elucidation of EWS-FLI1 associated transcription network modules. In-silico analysis of time-resolved expression data revealed enrichment of ETS binding motifs in early EWS-FLI1 activated target genes, while EWS-FLI1 repressed genes showed most prominently enrichment of recognition motifs for forkhead box (FOX) proteins. Other motifs significantly co-occurring in the same promoter with FOX motifs were mainly containing homeobox domains (POU, SOX, NKX, CDP, TGIF). Concentrating on the EWS-FLI1 repressed transcriptional network most FOX proteins (FOXO1, FOXO3, FOXD1 and FOXN3) in the data set were found to be EWS-FLI1 repressed. Promoters of two of these genes, FOXO1 and FOXO3, were directly bound by EWS-FLI1 in a ChIP-seq experiment, and were also expressed at lower levels in ESFT than in mesenchymal progenitor cells which constitute a likely cell of origin for ESFT. Furthermore, bioinformatic analysis showed that FOX motifs were significantly co-enriched with ETS motifs in promoters of the same gene for ∼4% of all genes. Thus, we hypothesize that EWS-FLI1 exerts a major part of its repressive effect via inhibition of FOX proteins and may also directly (co-)repress a subset of these genes. In depth dissection of this newly identified repressive module of the EWS-FLI1 transcription network is performed by ectopic expression, RNA interference (RNAi) and reporter gene technologies combined with mutation analysis, and chromatin immunoprecipitation and protein co-immunoprecipitation. This study was funded by: “European Embryonal Tumor Pipeline” 6th framework program of the European Commission, (STREP “E.E.T. Pipeline” contract LSHC-CT-2006-037260), and by funds from the Austrian Research Fund FWF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2009.
Abstract 3065: Loss of ARL11 function promotes growth of <i>in situ</i> neoplasia by activating the ras pathway
Authors: Sooyong Lee, Sangkyou Lee, Jolanta Bondaruk, Hua Wang, Shizhen Zhang, Menashe Bar-Eli, Peter Black, Colin Dinney, H. Barton Grossman, Margaret Knowles, Keith Baggerley, Bogdan Czerniak
Journal: Cancer Research (2010)

Abstract Our previously reported whole-organ genome-wide mapping studies of bladder cancer provided evidence that a new class of genes, referred to as forerunner (FR) genes (ITM2B, P2RY5, GPR38 and ARL11), located near known tumor suppressors such as RB1, may drive early clonal expansion of neoplasia. (S Lee, et al. PNAS 104: 13732-13737, 2007; T Majewski et al. Lab Inv 88: 694-712, 2008) These studies suggested three major steps for the involvement of the RB1 locus in tumor development. In the first step, one allele of FR gene and RB1 is inactivated by large deletions. In the second step, homozygous inactivation of the FR genes is accomplished by hypermethylation or less frequently by missence mutations. Homozygous inactivation of FR genes is associated with the clonal expansion of in situ lesions referred to as low-grade intraurothelial neoplasia. In the final, third step, the contiguous tumor suppressor, such as RB1, is inactivated most commonly by a mutation. This step is associated with clonal evolution into a transformed phenotype with microscopic features of carcinoma in situ progressing to invasive cancer. Recently, we concentrated our efforts on the ARL11 candidate FR gene, which encodes ADP-ribosylation factor-like 11 protein, a ras-related member of the small GTPases, that functions as GDP/GTP nucleotide interswitch for signal transduction. We have shown that it has been silenced by hypermethylation in approximately 40% of urothelial carcinomas of the bladder and the silencing was associated with in situ expansion of intraurothelial neoplasia. Moreover, loss of ARL11 expression was almost mutually exclusive with the FGFR3 mutations (&amp;lt;5% of bladder tumors showed a co-existence of mutant FGFR3 and methylated ARL11). Functional studies conducted on immortalized normal urothelial cells grown in vitro showed that ARL11 reduced cell proliferation, which was mediated by the inhibition of the ras pathway. This effect was associated with the down-regulation of the active ras and ERK1/2 phosphorylation as well as with the up-regulation of negative cell cycle regulator proteins such as p27kip1 and parallel down-regulation of cyclins D1 and E. Conversely, the silencing of ARL11 conferred a tumor suppressor effect promoting cell proliferation via the activation of the ras signaling pathway. In summary, our studies show that recessive events in the RB1 locus associated with the loss of ARL11 function promote clonal expansion of intraurothelial precursor lesions by activating the ras pathway in early occult phases of human bladder carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3065.
FRAILTY ASSESSMENT IN OLDER ADULTS UNDERGOING TRANSCATHETER OR SURGICAL AORTIC VALVE REPLACEMENT: THE FRAILTY-AVR STUDY
Authors: Jonathan Afilalo, Sandra Lauck, Dae Hyun Kim, Thierry Lefèvre, Nicolo Piazza, Kevin Lachapelle, Giuseppe Martucci, Andre Lamy, Marino Labinaz, Mark Peterson, Rakesh Arora, Nicolas Noiseux, Andrew Rassi, Igor Palacios, Philippe Généreux, Brian Lindman, Anita Asgar, Caroline Kim, Amanda Trnkus, Jose Morais, Yves Langlois, Lawrence Rudski, Jeffrey Popma, John Webb, Louis Perrault
Journal: Journal of the American College of Cardiology (2016)
Lidocaine in the Prevention of Sudden Death in the Pre-Hospital Phase of Acute Infarction
Authors: P.A. Valentine, J.L. Frew, M.L. Mashford, J.G. Sloman
Journal: New England Journal of Medicine (1974)

A double-blind study was undertaken to test the hypothesis that a prophylactic injection of 300 mg of lidocaine as a 10 per cent solution into the deltoid muscle would prevent death for two hours after injection during the pre-hospital phase of acute myocardial infarction. Two hundred and thirty-three Australian family physicians randomly administered lidocaine or placebo to their patients at the earliest suspicion of acute infarction. Patients over 70 years, with heart rate <56 beats per minute, systolic arterial pressure <91 mm Hg, or more than 12 hours of symptoms were excluded from the study. A total of 269 patients with either definite or possible infarction satisfied the criteria of the protocol. During the first two hours after injection three out of 156 lidocaine-treated and eight out of 113 placebo-treated patients died (p<0.03). Early prophylactic administration of lidocaine may decrease mortality during the pre-hospital phase of acute myocardial infarction. (N Engl J Med 291:1327–1331, 1974)
SP0190 Improving rheumatologic care and education in the republic of macedonia
Authors: V. Ognenovski
Journal: Annals of the Rheumatic Diseases (2013)

In 2009, ILAR (International League of Associations for Rheumatology) funded a project in Macedonia supporting establishment of national Rheumatoid Arthritis (RA) registry. An academic partnership between the rheumatology clinics at the University of Michigan and the University of Skopje was established allowing exchanges of rheumatologists, trainees and medical students. Results from this project pointed to unmet needs in patient access to qualified care and suboptimal therapy, among others. For RA patients, the average DAS-28 score was 5.2. All rheumatologists in Macedonia practice in the capital, with half of the population or over one million people without good access to rheumatologic care. Training additional rheumatologists from underserved regions and patient education were some of goals identified for improving access and quality of care for patients with rheumatic conditions. In 2011, ILAR funded a second project in Macedonia, supporting rheumatologic education for physicians from underserved regions and patient education. In a collaborative effort between the rheumatology clinics at the University of Michigan and the University in Skopje, an internist from the city of Bitola commenced training in rheumatology. A local rheumatology clinic has been established within the regional hospital, providing access and care for a region of 300,000 people. The candidate physician has been accepted for formal training at the rheumatology clinic in Skopje, pending approval from the ministry of health. A longitudinal data collection will address the impact of local care on patients with RA. Parallel to this effort, we launched an educational program for patients in partnership with the local patient advocacy group (NORA). We have produced 10 educational brochures on the most common rheumatic conditions for distribution across the country. Based on this model, partnership between academic centers in the developed countries and academic centers in the developing countries can promote rheumatologic education and care in the developing countries. Fostering close working relationship among individuals of academic centers, local patient advocacy groups, and local government agencies are critical components of this model. Potential funding resources include professional societies, local government agencies, pharmaceutical industry and philanthropy. The impact of this intervention should be assessed by metrics such as disease activity scores, patient satisfaction surveys and assessment of standard of care. Disclosure of Interest V. Ognenovski Grant/Research support from: ILAR, Consultant for: Roche
Abstract 1683: ATF4 down-regulation potentiates L-asparaginase activity in ovarian cancer cell lines
Authors: Philip L. Lorenzi, Jenny Llamas, Natasha J. Caplen, John N. Weinstein
Journal: Cancer Research (2010)

Abstract The enzyme-drug L-asparaginase (L-ASP) has been used for four decades to treat acute lymphoblastic leukemia. However, its unique mechanism of action is still poorly understood, and its clinical efficacy has proven unpredictable. Those problems have prompted a continuing search for biomarkers that predict L-ASP response. We previously found that the expression of asparagine synthetase (ASNS) is strongly correlated with L-ASP activity in leukemia cell lines of the NCI-60 cell line panel. Unexpectedly, however, the correlation was also apparent in ovarian cancer lines, suggesting that L-ASP might be effective against a low-ASNS subset of ovarian cancers if salient characteristics of the cell lines reflect clinical ovarian tumors. Using siRNA to down-regulate ASNS by 5-fold produced a proportional ∼5-fold potentiation of L-ASP activity in some ovarian cancer lines (OVCAR-3 and OVCAR-4). Surprisingly, ASNS siRNAs yielded a striking &amp;gt;500-fold potentiation in other ovarian lines (OVCAR-8 and OVCAR-8/ADR). Taken together, those findings suggest that the L-ASP/ASNS correlation is causal but also support the hypothesis that L-ASP activity is modulated by additional molecules or pathways. To address that hypothesis and to further elucidate the L-ASP mechanism of action, we have initiated genome-wide siRNA library screening. Preliminary screens in the OVCAR-8 cell line using a 418-gene apoptosis library, a custom 392-gene metabolic library, and the MTS assay as an endpoint yielded Z′ factors &amp;gt;0.90, indicating a robust screen. RNAi-mediated down-regulation of apoptosis genes had little or no effect on L-ASP's anticancer activity. That was surprising because L-ASP has been reported to cause apoptosis through glutamine depletion. Knock-down of ATF4, a transcription factor involved in cell metabolism, did markedly potentiate L-ASP activity (&amp;gt;500-fold). Furthermore, ATF4 knock-down markedly enhanced L-ASP anticancer activity toward the highly resistant cell line, OVCAR-4. These findings suggest that ATF4 is an important mediator of L-ASP resistance and provide rationale for investigation of ATF4 as a predictive biomarker of L-ASP effect. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1683.
Euthanasia, Physician-Assisted Suicide, and Other Medical Practices Involving the End of Life in the Netherlands, 1990–1995
Authors: Paul J. van der Maas, Gerrit van der Wal, Ilinka Haverkate, Carmen L.M. de Graaff, John G.C. Kester, Bregje D. Onwuteaka-Philipsen, Agnes van der Heide, Jacqueline M. Bosma, Dick L. Willems
Journal: New England Journal of Medicine (1996)

In 1991 a new procedure for reporting physician-assisted deaths was introduced in the Netherlands that led to a tripling in the number of reported cases. In 1995, as part of an evaluation of this procedure, a nationwide study of euthanasia and other medical practices concerning the end of life was begun that was identical to a study conducted in 1990.We conducted two studies, the first involving interviews with 405 physicians (general practitioners, nursing home physicians, and clinical specialists) and the second involving questionnaires mailed to the physicians attending 6060 deaths that were identified from death certificates. The response rates were 89 percent and 77 percent, respectively.Among the deaths studied, 2.3 percent of those in the interview study and 2.4 percent of those in the death-certificate study were estimated to have resulted from euthanasia, and 0.4 percent and 0.2 percent, respectively, resulted from physician-assisted suicide. In 0.7 percent of cases, life was ended without the explicit, concurrent request of the patient. Pain and symptoms were alleviated with doses of opioids that may have shortened life in 14.7 to 19.1 percent of cases, and decisions to withhold or withdraw life-prolonging treatment were made in 20.2 percent. Euthanasia seems to have increased in incidence since 1990, and ending of life without the patient's explicit request to have decreased slightly. For each type of medical decision except those in which life-prolonging treatment was withheld or withdrawn, cancer was the most frequently reported diagnosis.Since the notification procedure was introduced, end-of-life decision making in the Netherlands has changed only slightly, in an anticipated direction. Close monitoring of such decisions is possible, and we found no signs of an unacceptable increase in the number of decisions or of less careful decision making.
SAT0079 Mutual Associations among Musculoskeletal Diseases, Metabolic Syndrome, and Cognitive Impairment: A 3-Year Follow-Up of the ROAD Study
Authors: N. Yoshimura, S. Muraki, H. Oka, S. Tanaka, H. Kawaguchi, K. Nakamura
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> The leading cause of disability requiring support is cardiovascular disease, followed by dementia/cognitive impairment, senility, osteoarthritis (OA), and fall/osteoporotic fracture in Japan. However, no study has clarified the interactions between diseases causing disability. <h3>Objectives</h3> To assess the associations among diseases causing disability requiring support, including (i) musculoskeletal diseases (knee OA [KOA], lumbar spondylosis [LS], and osteoporosis [OP]); (ii) metabolic risk factors for cardiovascular diseases, including overweight (OW), hypertension (HT), dyslipidaemia (DL), and impaired glucose tolerance (IGT); and (iii) mild cognitive impairment (MCI). <h3>Methods</h3> Among 1,690 participants (596 men, 1,094 women) at the baseline, 1,384 individuals (81.9%; 466 men, 918 women) repeated the first follow-up in 2008 and completed blood, mini-mental state, and radiographic examinations, and measurement of bone mineral density. Logistic regression analysis was performed using occurrence or non-occurrence of the above-mentioned risk factors as the objective variable, after adjusting for confounders and presence or absence of the above-mentioned risk factors as explanatory variables. <h3>Results</h3> Risk of KOA occurrence increased significantly by presence of HT, IGT, and MCI (P=0.018, 0.042, and 0.043, respectively). Occurrence of OP of the femoral neck was inversely associated with OW (P=0.007). OW was influenced significantly by presence of KOA and MCI (P=0.001 for both). Risk of HT occurrence increased by presence of KOA and OW (P=0.030 and 0.021, respectively). IGT occurrence was influenced significantly by presence of OW (P=0.009). In contrast, occurrence of LS or DL was not influenced by factors of metabolic syndrome or musculoskeletal diseases. In addition, occurrence of MCI was not influenced by any other factor. <h3>Conclusions</h3> Presence of HT, IGT, and MCI significantly increased the risk of occurrence of KOA, and presence of KOA increased the risk of occurrence of HT and OW. Presence of OW decreased the risk of occurrence of OP. Diseases causing disability were clarified to be associated with each other. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3577