tbuckley/cabot-search huggingface dataset:
Abstract LB-146: A study of p16 inactivation in lung cancer cell lines and tumor samples with a meta-analysis of the literature
Authors: Kit W. Tam, Wei Zhang, Junichi Soh, Min Chen, Han Sun, Victor Stastny, Kelsie Thu, Wan Lam, Adi Gazdar
Journal: Cancer Research (2012)

Abstract Introduction: p16 inactivation is a common genetic alteration in lung adenocarcinoma and is often inactivated by homozygous deletion (HD) or methylation of promoter, or rarely by point mutation. While p16 methylation was reported to be linked to KRAS mutation and smoking, the association between specific p16 inactivation mechanism and other common genetic changes and smoking status remains controversial. In this study, we examined all of the three p16 inactivation mechanisms and correlated them with other common genetic chanes in lung adenocarcinoma: EGFR, KRAS, and LKB1, and smoking status. We also performed a meta-analysis to study the effect of smoking on p16 inactivation. Methods: We examined 40 cell lines and 45 tumor samples from patients with primary NSCLC, mostly adenocarcinoma. SNP and qPCR were used to detect HD. Methylation was determined by MSP analysis and mutation was identified by sequencing. We performed the meta-analysis by using Woolf's test to identify heterogeneity and followed by using a random-effect model. Results: The cell lines and tumor samples demonstrated similar results. No statistical differences were found between the two groups and the data were hence combined for analysis. p16 inactivation occurred at similar frequencies (54-57%) regardless of mutational status of EGFR, KRAS and LKB1 but the major mechanism of inactivation varied. Multivariate analysis showed that LKB1 inactivation was associated with p16 HD; p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. No significant association was established between any p16 inactivation mechanism and smoking status based on our data. HD was found to be the major mechanism of p16 inactivation among both smokers and never smokers although the rate of p16 methylation was higher in smokers. The result of our meta-analysis showed that p16 methylation was associated with smoking. The results from the literature were homogenous and the overall odds ratio from the meta-analysis was 2.01, which is significant at 0.05 level. Conclusions: p16 inactivation is a common event in lung adenocarcinoma and the inactivation mechanism of p16 is associated with other genetic changes and smoking status. Meta-analysis confirmed the association between p16 methylation and smoking. Our results indicate the presence of different pathways via p16 inactivation in the development of lung adenocarcinoma. 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 LB-146. doi:1538-7445.AM2012-LB-146
Abstract 2353: CREB regulates AP-2α transcription to determine the malignant phenotype of melanoma
Authors: Andrey S. Dobroff, Vladislava O. Melnikova, Gabriel J. Villares, Maya Zigler, Russell R. Braeuer, Hua Wang, Li Huang, Menashe Bar-Eli
Journal: Cancer Research (2010)

Abstract The Activator protein-2 (AP-2) family of transcription factors consists of five different proteins which are involved in the regulation of cell proliferation, differentiation, apoptosis and carcinogenesis. Among these proteins, AP-2α has been suggested to function as a tumor suppressor in many cancers including melanoma. We have previously shown that in melanoma cell lines, acquisition of the metastatic phenotype is associated with loss of AP-2α expression and gain in expression of cAMP-responsive element (CRE)-binding protein (CREB). This inverse correlation is associated with increase of melanoma invasion and metastasis resulting in overexpression of the melanoma cell adhesion molecule MCAM/MUC18 and protease-activated receptor 1 (PAR-1). However, the molecular mechanism involved in AP-2α regulation during melanoma progression remains unknown. Analyses of AP-2α promoter for transcription factor binding sites showed two distinct CRE-like sites as well as four E2F1 sites. Herein, we propose that the inhibition of AP-2α during the transition from the Radial Growth Phase (RGP) to the Vertical Growth Phase (VGP) occurs at the transcriptional level and is regulated through binding of CREB and E2F1. Hence, AP-2α protein expression was found to be increased after utilizing small hairpin RNA (shRNA) targeting CREB in two human metastatic melanoma cell lines, A375SM and C8161. Interestingly, E2F1 expression level was found to be reduced by 50% after CREB silencing in both cell lines. We also found a 20-fold increase in the luciferase activity driven by the AP-2α promoter after silencing CREB in both cell lines. In addition, point mutations at CRE-like binding sites as well as E2F1 increased the AP-2α promoter activity by more then 5-fold. To further establish the involvement of E2F1 in AP-2α regulation, we transiently overexpressed E2F1 in a low-metastatic melanoma cell line, SB-2. The AP-2α protein level as well as the promoter activity was significantly inhibited as compared to control. Finally, using Chromatin Immunoprecipitation (ChIP) assays in both CREB silenced cell lines, we were able to confirm that CREB and E2F1 bind to the AP-2α promoter thereby inhibiting its expression. Taken together, our studies demonstrate that CREB regulates AP-2α expression, thus, contributing to the metastatic phenotype of melanoma. 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 2353.
GE-29 * EXPRESSION SUBCLASS PROFILE IN PSEUDOPROGRESSION AND TRUE PROGRESSION IN NEWLY DIAGNOSED GBM
Authors: A. Robin, A. Raghunathan, D. Leung, C. Burmeister, L. Poisson, L. Scarpace, T. Walbert, T. Mikkelsen, I. Lee
Journal: Neuro-Oncology (2014)

INTRODUCTION: The hallmark of glioblastoma multiforme (GBM) is its penchant for relentless progression. Pseudoprogression describes a post-treatment reaction demonstrating increased edema and contrast enhancement similar to typical tumor progression except that on subsequent imaging without escalation of antitumor therapy these changes stabilize or revert [1]. Accurate identification of pseudoprogression has important implications for therapy and research and potentially prognosis as well. Increased cellular proliferation (Ki-67 indices) and the presence of a methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter have been associated with higher rates of pseudoprogression [2,3]. However, more sensitive and specific biomarkers of pseudoprogression are needed. This study seeks to identify novel indicators of pseudoprogression. METHODS: Patients were identified using the Hermelin Brain Tumor Center database at Henry Ford Hospital. Tissues from 52 patients with newly diagnosed GBM between 1992 and 2011 were gathered and whole genome sequencing and subtyping was performed by The Cancer Genome Atlas researchers. Retrospective chart review was carried out. Patients were assigned to either pseudoprogression (PP) or true progression (TP) groups based on whether changes suggestive of disease progression on MRI within 2 months of post-operative therapy initiation regressed without additional antitumor therapy during the ensuing 4 months. The incidence of pseudoprogression and GBM subclass were correlated using Fisher's Exact Test. RESULTS: Forty-one of 52 (79%) cases were identified as TP while 11/52 (21%) were found to have PP. In our study population, PP was associated with significantly increased median survival compared with TP (735 versus 313 days, respectively, p < 0.0012). The molecular subclass profile for both groups included a predominance of Mesenchymal and Neural subtypes, revealing no correlation between GBM subclass and the risk of pseudoprogression (p < 0.8069). CONCLUSIONS: Pseudoprogression correlated with improved survival. Interestingly, Mesenchymal and Neural GBM subclasses predominated in our PP group, suggesting a factor independent of molecular subclassification may predict pseudoprogression.
TRATAMIENTO ENDOSCÓPICO DEL DIVERTÍCULO DE ZENKER
Authors: S Parejo Carbonell, JR Foruny Olcina, V Defarges Pons, JA González Martín, E Vázquez Sequeiros, F Mesonero Gismero, C Senosiaín Lalastra, J Martínez González, D Boixeda De Miquel, A Albillos Martínez
Journal: Endoscopy (2013)

Introducción: En el manejo del divertículo de Zenker (DZ), la miotomía del cricofaríngeo guiada por endoscopia se ha propuesto como alternativa al tratamiento quirúrgico. Objetivo: Evaluar la eficacia y seguridad del tratamiento endoscópico del DZ empleando el sistema de sellado-corte tisular Ligasure®. Material y Método: Entre 2008 – 2013 se trataron 14 pacientes con DZ (7 varones). La mediana de edad fue 72 años (rango 36 – 89) y del tiempo de evolución de los síntomas 4 años (rango 1 – 20). Todos presentaban atragantamientos y disfagia (53,8% a semisólidos; 38,5% a líquidos; 7,7% afagia). Otros síntomas relevantes fueron regurgitación (84,6%), tos (30,8%) y neumonía aspirativa (7,7%). La mediana del tamaño diverticular fue 3 cm (rango 2 – 5). El procedimiento se realizó en régimen de hospitalización, con profilaxis antibiótica y bajo anestesia general (42.9%) o sedación (57.1%). Se empleó un diverticuloscopio (Wilson-Cook®) para exposición del septo diverticular, realizando la miotomía con pinza laparoscópica Ligasure®, bajo control con endoscopio ultrafino colocado en paralelo (6 mm; Pentax®EG-1870K). Resultados: Tras una mediana de seguimiento de 21 meses (rango 2 – 57), en el análisis por intención de tratar, se constató éxito clínico con tolerancia a sólidos en el 78.6%, mejoría parcial con disfagia ocasional a sólidos en el 14.3% y fallo de tratamiento en un paciente (7,1%), donde no fue posible utilizar Ligasure® por angulación del diverticuloscopio y se utilizó un esfinterotomo de aguja. Un paciente requirió reintervención endoscópica pasados 30 meses del primer tratamiento. Se registraron como complicaciones menores dolor cervical transitorio (4 pacientes/28.6%), fiebre (1 paciente/7.1%) y una complicación mayor consistente en perforación resuelta con tratamiento médico. Excluyendo al paciente que presentó perforación que requirió ingreso durante 14 días, la mediana del tiempo de hospitalización fue de 24h (rango 24 – 96). Conclusiones: El tratamiento del DZ con endoscopio flexible empleando el sistema de corte-sellado tisular Ligasure® es una técnica segura y eficaz que constituye una alternativa al tratamiento quirúrgico convencional.
Detection of Autoantibodies to Recombinant Mitochondrial Proteins in Patients with Primary Biliary Cirrhosis
Authors: Judy Van de Water, Anne Cooper, Charles D. Surh, Ross Coppel, Dean Danner, Aftab Ansari, Rolland Dickson, M. Eric Gershwin
Journal: New England Journal of Medicine (1989)

Primary biliary cirrhosis is characterized by the presence of autoantibodies to mitochondria with specific reactivity to proteins of 74 and 52 kilodaltons (kd). The 74-kd mitochondrial protein is the E2 component — dihydrolipoamide acetyltransferase — of the pyruvate dehydrogenase complex, and the 52-kd protein is the equivalent E2 component — dihydrolipoamide acyltransferase — of the branched-chain α-keto acid dehydrogenase complex. Current methods for the detection of antibodies to these proteins lack specificity or sensitivity, or they are time-consuming and not readily available. We therefore developed an enzyme-linked immunoassay to quantify specific antimitochondrial antibodies in patients with primary biliary cirrhosis. Recombinant polypeptides coding for both the 74-kd and the 52-kd mitochondrial autoantigens were used to analyze 217 coded serum samples, including samples from 93 patients with primary biliary cirrhosis and 124 controls, for reactivity by our immunoassay, immunoblotting, and immunofluorescence testing. Serum samples from 89 of the 93 patients with primary biliary cirrhosis reacted with either the pyruvate dehydrogenase-E2 or the branched-chain α-keto acid dehydrogenase protein. None of the 124 control samples from healthy volunteers (n = 86) or patients with primary sclerosing cholangitis (n = 38) had significant reactivity. Our results indicate that the use of recombinant, cloned autoantigens provides a simple, accurate, and rapid method of quantifying and monitoring the levels of specific mitochondrial autoantibodies in the serum of patients with primary biliary cirrhosis. (N Engl J Med 1989; 320: 1377–80.)
AB0097 Th17 Cytokines Regulate Osteoclastogenesis in Rheumatoid Arthritis
Authors: H.R. Kim, S.-H. Lee
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Th17 cells, which are defined by a selective interleukin (IL)-17 secretion, are involved in the bony destruction of rheumatoid arthritis (RA). <h3>Objectives</h3> This study aimed to determine the regulatory effect of Th17 cytokines on the osteoclastogenesis in RA. <h3>Methods</h3> The expression of IL-17 and RANKL was determined in synovial tissue, fibroblast-like synoviocytes (FLS) and synovial fluids of RA patients using immonohistochemical staining, ELISA and real-time PCR. The Th17 cytokines-induced RANKL expression was studied in RA FLS using real-time PCR, luciferase activity, and western blot. Human peripheral blood monocytes were cultured with M-CSF and Th17 cytokines, and then osteoclastogenesis was determined by counting the number TRAP-positive multinucleated cells. The osteoclastogenesis was also determined after human monocytes were co-cultured with IL-17-prestimulated FLS. <h3>Results</h3> There was significant correlation between RANKL and IL-17 levels in RA synovial fluid. After RA FLS were stimulated with IL-17, IL-21 and IL-22, the expression of RANKL mRNA increased and the IL-17-induced RANKL expression was decreased by the inhibition of Act1, TRAF6, NF-κB and the AP-1. Th17 cytokines and IL-17-prestimulated FLS induced osteoclastogenesis from monocytes in the absence of osteoblasts or RANKL. <h3>Conclusions</h3> Th17 cytokines have a dual effect on osteooclastogenesis in RA; direct induction of osteoclastogenesis from monocytes and upregulation of RANKL production in RA FLS. Th17 cytokines/RANKL axis could be a potential therapeutic target for bone destruction in RA. <h3>References</h3> McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends in immunology. 2006;27(1):17-23. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. The Journal of clinical investigation. 1999;103(9):1345-52. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L, et al. Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis and rheumatism. 1999;42(5):963-70. <h3>Acknowledgements</h3> NONE <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1977
Primary Amebic Meningoencephalitis
Authors: Richard J. Duma, Harold W. Ferrell, E. Clifford Nelson, Muriel M. Jones
Journal: New England Journal of Medicine (1969)

A healthy 15-year-old girl suffered fatal meningoencephalitis due to free-living amebas identified as naegleria. The organisms were cultured from cerebrospinal fluid, brain, lung, liver and spleen, and were seen in heart blood. Acute, diffuse myocarditis complicated by pulmonary edema occurred and was believed to be related to the infecting amebas. Primary amebic meningoencephalitis is being recognized with increased frequency and appears to be worldwide and capable of producing epidemics. Patients often give a history of swimming in fresh or brackish water, and the portal of entry may be the nasal mucosa. By means of appropriate technics, isolation of free-living amebas is relatively simple. All isolates (Florida, Virginia, Australia and Czechoslovakia) have been naegleria. The disease appears to be universally fatal and at present without promise of therapy.
Total Adrenalectomy for Reactivated Carcinoma of the Prostate
Authors: J. Hartwell Harrison, George W. Thorn, Dalton Jenkins
Journal: New England Journal of Medicine (1953)

AN effective new approach to the treatment of neoplastic disease was provided by Huggins and Hodges1 when they demonstrated the control of cancer of the prostate by orchiectomy and the administration of estrogens. Simultaneously, Munger2 achieved a similar though less effective result by radiation of the testes. During the last ten years extensive confirmation of the value of these contributions has been obtained. However, subsequent reactivation of cancer of the prostate after inhibition by hormonal therapy has been a consistent and challenging aspect of the course of the disease. Following the logical assumption that androgens are an activating factor in . . .
EVEN MILD AORTIC REGURGITATION A RISK FOR MORTALITY AFTER TRANS-CATHETER AORTIC VALVE REPLACEMENT
Authors: Brandon M. Jones, E. Murat Tuzcu, Amar Krishnaswamy, Zoran Popovic, Stephanie Mick, Lars Svensson, Samir Kapadia
Journal: Journal of the American College of Cardiology (2015)
Abstract 5230: Improving the specificity of drugs which target the actin cytoskeleton for cancer therapy
Authors: Vanessa B. Sequeira, Justine R. Stehn, Nikolas Haass, Teresa Bonello, Kim Guven, Melissa Desouza, Galina Schevzov, Gregg Kottyan, Adam McCluskey, Leanne Bischof, Stephen Palmer, Edna C. Hardeman, Munif Allanson, Vivienne Reeve, Wolfgang Weninger, Timothy P. Cripe, Peter Gunning
Journal: Cancer Research (2012)

Abstract The actin cytoskeleton is fundamental in the regulation of cellular processes involved in tumourigenesis and is therefore a highly desirable chemotherapeutic target. However, the non-specific nature of actin-targeting drugs makes them ineffective due to their toxic action on the heart. We have designed a class of drugs that target the second core component of actin filaments, tropomyosin. Tm5NM1, a cytoskeletal tropomyosin isoform, is upregulated in a variety of tumour cells and patient samples, and is known to promote tumour cell growth. Our lead drug, TR100, targets Tm5NM1 and potentially other isoforms, reducing cell proliferation in vitro in a panel of melanoma and neuroblastoma cell lines and decreases the rate of tumour growth in vivo in melanoma and neuroblastoma mouse models without affecting heart integrity. The difficulty in improving the specificity of these anti-tropomyosin compounds for Tm5NM1 was the lack of a suitable cell-based system to test the drugs. NIH3T3 stable cells overexpressing fluorophore-tagged Tm5NM1 or the muscle-specific isoform αfastTm now allows us to determine the impact of our drugs on functionally distinct actin populations. Since tropomyosin is a structural protein with no known measurable catalytic activity it has previously been challenging to design a high throughput assay to quantitate specific changes in actin filament architecture. High content imaging provides a system to image actin filament integrity which can be quantified using an algorithm designed in collaboration with the CSIRO. Using this algorithm we can calculate the impact of the anti-tropomyosin compounds on actin filaments in co-cultured stable cells. Development of these assays will contribute to the design of more specific drugs which target defined tropomyosin containing actin populations highly expressed in cancer without showing toxicity in muscle, thereby improving the therapeutic index of anti-tropomyosin drugs for the clinical treatment of a wide array of cancers. 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 5230. doi:1538-7445.AM2012-5230
Understanding and improving water sanitation practices to improve health outcomes in Malawi
Authors: Penelope A Muelenaer, Kerry J Redican, Susan W Marmagas, Rochelle H Holm
Journal: The Lancet Global Health (2016)

Background Sustainable Development Goals (SDG) for the universal provision of safe drinking water in the household focus on the need for sustainable, effective, and acceptable household water treatment. In this study we aimed to: understand baseline practices and knowledge related to household water supply, safety of drinking water, and hygiene and sanitation; and compare the efficacy and acceptance of three different point-of-use water treatment interventions.
Abstract 4228: A functional role of OCT4 for prostate tumor initiation
Authors: Douglas E. Linn, Xi Yang, Feng Sun, Yingqiu Xie, Saranya Chumsri, Angelika Burger, Yun Qiu
Journal: Cancer Research (2010)

Abstract We have established several drug resistant prostate cancer cell lines by long term culturing hormone refractory CWR-R1 cells in medium containing chemotherapeutic drugs. These cells displayed a significant increase in side-population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1. To further characterize drug resistant CWR-R1 prostate cancer cell lines, we performed microarray analysis on two drug resistant cell lines in comparison with the drug sensitive parental line. Our Ingenuity pathway analysis suggested that OCT4/POU5F1, the key transcription factor for regulating pluripotency in embryonic stem cells, was upregulated in the drug-resistant lines compared to the parental cells, which was accompanied with transcriptional activation of a set of OCT4 known target genes. Upregulation of OCT4 in drug resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmed by western blot and specific shRNA knockdown. Analysis of the regulatory region of OCT4 gene revealed that drug-resistant cell lines had reduced methylation compared to the parental line. Furthermore, these drug resistant cells exhibited a significant increase in transformation activity in vitro and tumorigenicity in vivo. Subcutaneous inoculation of as few as ten drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions. Our data suggest that these drug resistant cells may be enriched for tumor initiating cells. Knock-down OCT4 expression in drug-resistant cells by the specific shRNA resulted in a considerable decrease in growth both in vitro and in vivo. Our data suggest that OCT4 may play an essential role in promoting tumor initiation of prostate cancer cells. 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 4228.