tbuckley/cabot-search huggingface dataset:
STRUCTURAL VARIANTS SHUFFLE CHROMATIN TO ACTIVATE GFI1 FAMILY ONCOGENES IN MEDULLOBLASTOMA
Authors: P. A. Northcott, C. Lee, T. Zichner, P. Lichter, J. O. Korbel, R. J. Wechsler-Reya, S. M. Pfister
Journal: Neuro-Oncology (2014)

BACKGROUND: Genomics has illuminated the extensive intertumoural heterogeneity of medulloblastoma and identified at least four distinct molecular subgroups of the disease. Group 3 and Group 4 subgroup medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Exome and genome sequencing studies have confirmed a paucity of recurrent gene-level mutations in Group 3 and Group 4, suggesting that alternative oncogenic mechanisms must account for the large fraction of cases that cannot currently be explained by single-nucleotide variants or insertions/deletions alone. METHODS: Analysis of whole-genome sequencing data consisting of 128 primary Group 3 and Group 4 medulloblastoma samples facilitated a systematic, high-resolution screen for chromosomal breakpoints recurrently targeting novel medulloblastoma drivers by structural variation. A non-overlapping set of 22 medulloblastomas was sequenced by long-range paired-end mapping in order to validate structural variants observed in our discovery cohort. Select cases of interest were also investigated at the epigenome-level using a combination of whole-genome bisulphite sequencing and enhancer histone mark ChIP-sequencing. RESULTS: Our systematic analysis of structural variants identified highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation, including duplications, deletions, inversions, translocations, and other complex genomic variants were observed in nearly all GFI1/1B-activated cases. Comprehensive characterization of these structural variants established that GFI1/GFI1B expression becomes activated through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Functional analyses performed in mice confirmed the oncogenicity of Gfi1/Gfi1b in the context of medulloblastoma and demonstrated apparent synergy between both of these candidates and the c-Myc oncogene. CONCLUSIONS: These studies establish GFI1 and GFI1B as novel, highly prevalent medulloblastoma oncogenes specifically active in Group 3 and Group 4. Given their high frequencies of activation, GFI1 and GFI1B represent excellent candidates for prioritization of molecularly targeted therapy aimed at treatment of a significant proportion of Group 3 and Group 4 medulloblastoma patients. SECONDARY CATEGORY: Pediatrics.
Abstract 3121: Study of leukemia inhibitory factor (LIF) system in a murine mammary tumor comprising luminal and myoepithelial cells
Authors: Martin A. Krasnapolski, Ana Quaglino, Edith Kordon, Elisa D. Bal de Kier Joffe
Journal: Cancer Research (2011)

Abstract The presence of LIF, a cytokine that activates JAK/STAT and ERK pathways, its receptor (LIFRb) and the constitutive activation of Stat3 (a molecule downstream LIFRb) have been described in tumors, primary cultures and several cancer-derived cell lines, suggesting a role for this pathway in tumor progression. Also, Stat3 activation was widely related to an immunosuppressive phenotype in many tumor models. From the murine mammary adenocarcinoma M38 comprising luminal (LEP) and myoepithelial (MEP) cells (both transformed) we derived LM38-LP (LEP &amp; MEP), LM38-HP (epithelioid) and LM38-D2 (MEP) cell lines. While the mixed cell line presents a malignant behavior, the last two show a lower growth rate and metastatic potential than the parental tumor. Previously we demonstrated that this lower malignancy is partially caused by their inability to suppress the host's immune system, underscoring the importance of cellular interactions in complex tumor behaviors. Our purpose was to evaluate LIF and LIFRb mRNA expression levels and to study LIF effects on Stat3 and ERK activation, as well as on the proliferation and clonogenic capacity in the LM38 family of cell lines. Using RT-PCR we could see that LM38-LP cell line expresses high LIF and LIFRb mRNA levels, LM38-HP expresses LIF mRNA but not it receptor's mRNA and LM38-D2 has low levels of both molecules. By Western blot we studied LIF (80 ng/ml) effect over Stat3 and ERK activation. While in LM38-LP and LM38-D2 cells Stat3 and ERK phosphorylation was rapidly induced at 5 min, in LM38-HP cells, that don't express LIFRb, no response was detected. Then, we evaluated the effect of a prolonged 48 h treatment with LIF (1, 5, 20 and 80 ng/ml) on cell viability using MTS assay. While LIF slightly reduced cell viability (20%) in LM38-LP and LM38-D2 cell lines, LM38-HP cells were not affected. Finally, since LIF is also involved in stem cell maintenance, the effect of LIF in a low density/clonogenic setting was evaluated. While in LM38-LP and LM38-D2 cell lines LIF significatively (p&amp;lt;0.05) increased the number of colonies, LM38-HP cells were unaffected. We can conclude that LIF could be involved in LEP-MEP interaction and although it induced a subtle viability reduction, LIF could be nevertheless promoting tumor progression by increasing the number of clonogenic cells. In addition, LIF-induced Stat3 activation could be the responsible of the immunosuppresive characteristics of the mix tumor cell line, a proposal that deserves future studies. 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 3121. doi:10.1158/1538-7445.AM2011-3121
Abstract 1716: Calcitriol and progesterone synergistically inhibit growth in endometrial cancer cells.
Authors: Laura R. Lee, Brian L. Hood, Huyen Nguyen, Leyla Kavandi, Jane M. Turbov, Larry G. Thaete, Chad A. Hamilton, Gustavo C. Rodriguez, George L. Maxwell, Thomas P. Conrads, Viqar Syed
Journal: Cancer Research (2013)

Abstract Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. The combined cell treatment enhanced vitamin D receptor expression and synergistically inhibited cell proliferation through caspase-3 activation and induction of G0/G1 cell cycle arrest with associated down-regulation of cyclin D1, D3 and p27 induction. We used mass spectrometry-based proteomics to measure protein abundance differences between calcitriol-, progesterone-, or combination-exposed endometrial cells. A total of 117 proteins showed differential expression amongst these three treatments. Four proteins were then selected for validation studies: histone H1.4 (HIST1H1E), histidine triad nucleotide-binding protein 2 (HINT2), interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2), and Bcl-2-associated X protein (BAX). Abundance levels of selected candidates were low in endometrial cancer cell lines versus the immortalized endometrial epithelial cell line. All four proteins displayed elevated expression in cancer cells upon exposure to calcitriol, progesterone or the combination. Further BAX analysis through gain or loss of function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX:Bcl2 ratio. Knock down of BAX attenuated progesterone- and calcitriol-induced cell growth inhibition. Our results showed that progesterone and calcitriol up-regulate the expression of BAX along with other apoptosis-related proteins, which induced inhibition of endometrial cancer cell growth by apoptosis and cell cycle arrest. Citation Format: Laura R. Lee, Brian L. Hood, Huyen Nguyen, Leyla Kavandi, Jane M. Turbov, Larry G. Thaete, Chad A. Hamilton, Gustavo C. Rodriguez, George L. Maxwell, Thomas P. Conrads, Viqar Syed. Calcitriol and progesterone synergistically inhibit growth in endometrial cancer cells. [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 1716. doi:10.1158/1538-7445.AM2013-1716
EFFICACY AND SAFETY OF SHORT COURSES OF LOW-FREQUENCY ELECTRIC MYOSTIMULATION IN PATIENTS HOSPITALIZED FOR DECOMPENSATED CHRONIC HEART FAILURE
Authors: Viktoria Sviridenko, Maria Poltavskaya, Abram Syrkin, Artem Doletsky, Ilia Giverts, Oxana Dikur
Journal: Journal of the American College of Cardiology (2015)
Abstract 1822: Age-period-cohort (APC) analysis of primary bone cancer incidence rates in the United States (1976 – 2005)
Authors: Kristin P. Anfinsen, Freddie I. Bray, Rebecca Troisi, Thora J. Jonasdottir, Oyvind S. Bruland, Susan S. Devesa, Tom Grotmol
Journal: Cancer Research (2010)

Abstract BACKGROUND: Primary bone cancer comprises three major histological subtypes: osteosarcoma (OS), Ewing sarcoma (ES) and chondrosarcoma (CS). The most frequent subtype, OS, primarily occurs in adolescence, but has a second peak at the oldest ages, usually attributed to late effects of radiotherapy and chemotherapy, and Paget's disease. The adolescent age distribution of ES resembles that of OS, suggesting a link between the onset of puberty and these subtypes of bone cancer. CS is rare in childhood, and incidence rates, unlike those of OS and ES, increase fairly uniformly with age. Given the limited knowledge about the etiology of primary bone cancer, and the unusual age-incidence distribution for OS and ES, we undertook an APC analysis to determine whether incidence varied by birth cohort or calendar period. For other cancers, such as testis and breast, the identification of cohort patterns has generated new hypotheses regarding environmental risk factors. METHODS: We fit an APC model to incidence data among U.S. whites for OS, ES and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results (SEER) program, which covers about 10% of the U.S. population, 1976-2005. The purpose was to examine the temporal development of each bone cancer subtype, with an aim to providing etiologic clues as to the role of birth cohort-related changes. RESULTS: Incidence of OS decreased between 1976 and 2005 among those 60 years and older, and rates declined among cohorts born 1905-34. The risk of CS doubled among females 20-69 years, with rates increasing among consecutive birth cohorts born 1925-54, whereas those of males were unaltered. For both sexes, ES incidence rates tended to be stable. CONCLUSIONS: The risk reduction in OS at older ages was most likely due to improved radiotherapy and more effective chemotherapy. The CS risk increase in females corresponds to birth cohorts who were increasingly exposed to estrogens, both in terms of contraceptives (from 1960 onwards), and hormone replacement therapy (from 1950 onwards). In support of our hypothesis that estrogens are involved in the increase in CS among women over time, in vitro studies show that the estrogen signaling pathway stimulates proliferation of both normal and malignant chondrocytes. Further studies are warranted to pursue the possible etiological significance of estrogen exposure in CS risk. 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 1822.
AB0115 Non-Canonical Nf-κB Signaling Enhances Angiogenesis in A Novel 3D Model of Rheumatoid Arthritis Synovial Inflammation
Authors: C. Maracle, A.-R. Noort, K. van Zoest, S. Tas
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Angiogenesis plays a crucial role in the progression of rheumatoid arthritis (RA) and is considered a switch from acute to chronic inflammation. Previously, we have demonstrated that NF-κB inducing kinase (NIK) mediated activation of the non-canonical NF-κB pathway in endothelial cells (EC) induces angiogenesis. To further investigate the role of this pathway in RA angiogenesis, we developed an innovative 3D model that incorporates both EC and RA fibroblast-like synoviocytes (FLS) with the option to also add immune cells, thereby generating a model more representative of synovial angiogenesis. <h3>Objectives</h3> To develop a novel 3D <i>in vitro</i> model to study the interaction between RA FLS, EC and immune cells to further delineate the role of the non-canonical NF-κB pathway in pathological angiogenesis. <h3>Methods</h3> In the traditional 2D model, RA FLS and HUVEC were co-cultured with or without the non-canonical NF-κB signaling inducing stimuli lymphotoxin α1β2 (LT) and LIGHT, or VEGF as a positive control. EC were visualized through immunohistochemical staining of CD31. In the novel 3D model, spheroids of HUVEC and RA FLS, pre-incubated with green or orange cell tracker dye, were plated in a collagen solution with medium containing LT, LIGHT or bFGF/VEGF. After 48 hours, spheroids were imaged through confocal microscopy. Cumulative EC sprout length and the number of sprouts was quantified using Leica QWin Plus software. <h3>Results</h3> In the 2D model, LIGHT induced a significant increase in EC proliferation (p&lt;0.05) and the LT-induced increase neared significance (p=0.08). Confocal analysis of the 3D model showed that spheroids containing HUVEC and RA FLS formed sprouts under all conditions. Importantly, both LT and LIGHT caused significant increases (p&lt;0.05) in cumulative sprout length and total number of sprouts, which was comparable to that of bFGF/VEGF. Preliminary results indicate that siRNA-mediated targeting of NIK inhibits this process effectively. <h3>Conclusions</h3> We demonstrate that induction of non-canonical NF-κB signaling by LT or LIGHT enhances angiogenic responses in EC in both models. However, the new 3D model allows visualization of actual blood vessel formation and incorporation of immune cells in future studies. Based on our findings, targeting NIK may be a novel therapeutic approach to block pathological angiogenesis in RA, thereby halting disease progression. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5265
Biomarkers of Oxidative Stress in Breast Cancer.
Authors: R. Jassal, D. Talwar, D. Mcmillan, S. Tovey
Journal: Cancer Research (2009)

Abstract INTRODUCTIONDespite significant improvements in cancer diagnosis and treatment, approximately one-quarter of breast cancer patients will die of their disease. Oxidative stress has been implicated as a contributory factor in the development of breast cancer. Reactive oxygen species can initiate lipid peroxidation, resulting in generation of reactive secondary products which can induce oxidative DNA damage and mutations in the p53 tumour suppressor gene, which is one of the most frequent mutations associated with breast cancer development. Oxidative stress has also been associated with activation of transcription factors and tamoxifen resistance. The aim of the present study was to identify the levels of lipid peroxdation products; malondialdehyde and 8-iso-Prostaglandin F2α (8-iso-PGF2α), in patients with primary operable breast cancer, and to correlate these levels with pathological factors of disease including tumour grade, ER and HER2 status and also Nottingham prognostic index (NPI) status.METHODS:89 patients with primary operable breast cancer and 10 healthy subjects were studied. Plasma levels of MDA (total and free) and 8-iso-PGF2α were measured.RESULTS:The majority of patients were over 50 years (87%), had grade II/III tumours (68%), were axillary lymph node positive (41%) and had ER-positive tumours (82%). Compared to the control, patients had higher levels of total MDA (p&amp;lt;0.001), free MDA (p&amp;lt;0.001), and 8-iso-PGF2α (p&amp;lt;0.001). Both free (p&amp;lt;0.05) and total MDA (p=0.001) were significantly correlated with increasing tumour grade. Furthermore, total MDA levels were also associated with increased tumour size (p&amp;lt;0.05) and ER-negative tumours (p&amp;lt;0.05). Taken together, both total (p&amp;lt;0.001) and free (p &amp;lt;0.05) MDA were significantly associated with higher NPI categories. 8-iso-PGF2α showed only a correlation with increasing age (p&amp;lt;0.05)CONCLUSION:The present study shows that patients with breast cancer have evidence of increased levels of oxidative stress. Furthermore, MDA concentration was significantly associated with conventional markers of poor prognosis. This data suggests oxidative stress may be involved in tumour progression to a more aggressive phenotype. Thus MDA maybe a useful marker of tumour associated oxidative damage and may provide a promising marker for risk prediction and targets for preventative measures in breast cancer patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2141.
Phagocytosis in Chronic Granulomatous Disease and the Chediak–Higashi Syndrome
Authors: Thomas P. Stossel, Richard K. Root, Martha Vaughan
Journal: New England Journal of Medicine (1972)

Phagocytosis of emulsified paraffin oil containing oil red O by blood leukocytes from three male patients with chronic granulomatous disease was not abnormal, whereas the phagocytic rate and capacity of leukocytes from two patients with the Chediak-Higashi syndrome were doubled in relation to normal cells. The specific activities of acid hydrolases and peroxidase in whole homogenates or in oil-laden phagocytic vesicles isolated by flotation from normal leukocytes or those from patients with chronic granulomatous disease were similar. Specific activities of β-glucuronidase and peroxidase in vesicles obtained from leukocytes in the Chediak-Higashi syndrome were 56 to 67 per cent of normal, but activities of acid and alkaline phosphatases in the vesicles and of all the enzymes assayed in whole homogenates were normal. By direct quantification, therefore, the extent of degranulation by leukocytes of patients with chronic granulomatous disease is not impaired, whereas a possible selective degranulation defect has been detected in those of patients with the Chediak - Higashi syndrome.
SP0143 Cholesterol and Steroidogenesis in Chronic Inflammation
Authors: R. H. Straub
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Cholesterol is the starting point of synthesis of steroid hormones and vitamin D. Thus, its uptake, storage, transport, and conversion into respective downstream hormones is of outstanding importance. Cholesterol is taken up into the cell by the cholesterol uptake receptor SR-BI. In adrenal glands, it is stored as cholesterol ester in vesicles that gives the organ its characteristic yellow color. Cholesterol ester is degraded by lipases on demand. Cholesterol ester is transported into mitochondria where it is converted into pregnenolone, the starting point of steroidogenesis. Pregnenolone is converted into a multitude of downstream hormones with the major pathways leading to mineralocorticoids, glucocorticoids, and adrenal androgens. In chronic inflammatory diseases, these pathways are altered so that the major pathway to glucocorticoids is up-regulated at the expense of adrenal androgens. Nevertheless, the amount of secreted glucocorticoids is inadequate in relation to systemic inflammation leading to relative insufficiency. In the animal model of experimental arthritis, we recently demonstrated mitochondrial defects in the chronic phase of the disease which most probably contributes to inadequate low levels of glucocorticoids in relation to inflammation. This presentation highlights defects and alterations in steroidogenesis. These alterations belong to an adaptive program positively selected for short-lived inflammatory episodes but not for chronic life-long inflammation. <h3>Disclosure of Interest</h3> None Declared
RESULTADOS DE UNA ENCUESTA SOBRE EL PRIMER CURSO UNIVERSITARIO (VIRTUAL Y PRESENCIAL) DE ECOENDOSCOPIA
Authors: MJ Varas, X Aldeguer, C Loras, JB Gornals, F Muñoz, R Abad, J Esteban
Journal: Endoscopy (2011)

Introducción: En el aprendizaje de la USE se recomienda un periodo de formación supervisada de 6–12 meses, y la práctica de 150 a 190 procedimientos (ASGE 2001). Existen pocos cursos universitarios especializados en Europa y ninguno en España.
Chemotherapy's Benefits Bring Hope of Progress for NSCLC
Authors: T. Reynolds
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Chemotherapy's Benefits Bring Hope of Progress for NSCLC 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 87, Issue 22, 15 November 1995, Pages 1661–1662, https://doi.org/10.1093/jnci/87.22.1661 Published: 15 November 1995
SAT0452 Response matters in rheumatoid arthritis: improvements in patient resource use, activities of daily living and employment are only significant if remission is achieved:
Authors: C. Barnabe, A.S. Russell, S.G. Barr, J. Homik, L. Martin, W.P. Maksymowych
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Improved productivity has been observed for rheumatoid arthritis (RA) patients achieving a good response with anti-TNF therapy. We hypothesized that the magnitude of improvement in patient-level resource use indicators may be affected by the degree of treatment response. <h3>Objectives</h3> To evaluate resource use, engagement in activities of daily living (ADLs), and employment status by level of disease activity in anti-TNF therapy in RA. <h3>Methods</h3> The Alberta Biologics Pharmacosurveillance Program evaluates the longitudinal clinical efficacy and safety of anti-TNF therapy for RA. Patients report every 6 months on their resource use (hospital services, community services, out-of-pocket costs), ADLs, and changes in employment status. We compared differences in resource use reported in the first year of treatment between patients achieving any definition of remission (2011 ACR/EULAR Boolean definition, SDAI ≤3.3, CDAI ≤2.8, DAS28 ≤2.6), minimal disease activity (DAS28 &lt;2.85, SDAI &lt;11 or CDAI &lt;10) or remaining in moderate or high disease activity. <h3>Results</h3> A total of 1,777 patients (70% female, disease duration 12 years, median DMARD exposure 3) initiated a new biologic therapy between April 2004 and March 2010. Baseline disease activity scores were: HAQ 1.15 (SD 0.76), DAS28 4.36 (SD 1.90), tender joint count 7.1 (SD 8.2), swollen joint count 4.7 (SD 5.5), and patient global 4.6 (SD 2.8). Over the first year of biologic therapy, 556 individuals met remission criteria (31%), and an additional 393 (22%) met minimal disease activity criteria, with the remainder remaining in moderate or high disease activity. Patients attaining remission, relative to those remaining in moderate or high disease activity, had significant improvements in resource utilization, engagement in ADLs and work productivity (Table 1). Patients only achieving minimal disease activity had similar resource use, impairments in activities of daily living and employment status compared to patients in moderate or high disease activity. <h3>Conclusions</h3> Patients achieving remission, relative to patients remaining in minimal, moderate or high disease activity, have significant reductions in resource use, have increased engagement in activities of daily living, and improved productivity. Treatment goals advocating remission over minimal disease activity are encouraged. <h3>Disclosure of Interest</h3> None Declared