tbuckley/cabot-search huggingface dataset:
Abstract B45: Epigenetic signature of human breast cancer subtypes
Authors: Sunita Badola, Alexander Parker, Mara Campbel, Michael Boedigheimer, Barbara Grubinska, Susan Turci, Kim Tsui, Michael A. Damore, Cindy A. Wilson
Journal: Cancer Research (2009)

Abstract Gene expression profiling has been used to extend classification of human breast cancers into five main sub-types having distinct clinical outcomes. The established prognostic markers ER, PR and HER-2 remain prominent components of this refined scheme that delineates luminal (luminal A, luminal B and HER-2) from non-luminal (basal/BRCA1 mutant and normal-like) breast cancers. Gene expression combined with immunohistochemical localization of various tumor markers in the normal mammary gland support the hypothesis that luminal and non-luminal breast tumors originate from different cell types. In the current study we explore epigenetic determinants of the different breast cancer sub-types using the genome-wide DNA methylation patterns (Illumina Infinium) of fifty human breast cancer cell lines. Principal component analysis of baseline gene expression profiles (Agilent) showed a clear separation between the luminal and non-luminal sub-types in agreement with previously published studies using a largely overlapping panel of breast cell lines. Comparative marker selection analysis using the GenePattern analysis package was then performed independently on the DNA methylation and gene expression datasets. When the results of these two analyses were compared, a statistically significant reciprocal overlap of the selected markers was observed. These results strongly suggest that a large fraction of the most robust luminal gene expression classifiers are silenced by promoter methylation in non-luminal cells, and conversely that many of the best non-luminal classifiers are silenced in luminal cells. The classifier genes indentified in the breast cancer cell line panel include the most highly referenced luminal (KRT8, ESR1, AR, TFF1, TFF3, TOB1 and XBP-1) and non-luminal markers (DSC3, VIM, SFRP1, KRT5, KRT16, KRT17, and RUNX3 that have been used to classify primary breast cancers. These striking differences in DNA methylation patterns strengthen the hypotheses that luminal and non-luminal sub-types arise from different precursor cells and that their transcriptional programs may be largely established during the process of cell specification in the mammary epithelial bi-layer. Since CpG island methylation is stable and robustly preserved in archival tissues, it is likely that a methylation signature comprised of a few key genes could be used to, for example, identify poor-prognosis, basal-type breast cancers. It is also possible that such a test would be more quantitative, accurate and reproducible than the “triple-negative” diagnosis currently based on the absence of immumohistochemical staining for ER, PR and HER-2. Citation Information: Cancer Res 2009;69(23 Suppl):B45.
SAT0423 Knee Osteoarthritis in Type 2 Diabetes Mellitus: Does Insulin Therapy Retard the Osteophyte Formation?
Authors: K.F. Aljarallah, D. Shehab, N. Abdulla, H. Al Mohamedy
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Despite many reports on the anabolic effects of insulin on connective tissue and cartilage metabolism in diabetes, data relating to the effect of insulin therapy in the progression of osteoarthritis (OA) is sparse. <h3>Objectives</h3> To investigate whether radiographic changes in knee OA in Type 2 diabetes mellitus (T2DM) patients on insulin treatment differed from those not on insulin. <h3>Methods</h3> A cross-sectional study was performed in 311 subjects (211 T2DM patients and 100 control subjects without diabetes), screened over a period of one year in a hospital-based setting. Patients were categorized into three groups, T2DM patients not on insulin (G1, n=99), T2DM patients on insulin (G2, n=112) and non-diabetic control group (G3, n=100). Plain X-ray of knee was used to assess the changes of knee OA and graded using Kellegren-Lawrence (K-L) scale and the Osteoarthritis Research Society International (OARSI) Atlas grading scale. <h3>Results</h3> A total of 622 knee X-rays were evaluated. A highly significant association (p&lt;0.001) was observed for OARSI-Joint Space Narrowing (JSN) as well as for osteophyte formation between the three groups. Comparing G2 and G3, highly significant association (p&lt;0.001) was retained for JSN and for osteophyte formation. Comparing G1 and G2, though there was no association (p&gt;0.05) for JSN, significantly lesser osteophytes formation were noted in T2DM G2 patients compared to T2DM G1 patients (11.7% vs. 19.7%, p=0.02). Multivariate logistic regression analysis showed that T2DM G2 group had less osteophyte formation than both G1 T2DM group and G3 control group, (odds ratio =0.294, p&lt;0.008 and odds ratio =0.098, p&lt;0.001, respectively) after inclusion of confounders such as age, gender and BMI. <h3>Conclusions</h3> Our findings suggest that insulin therapy might retard the radiographic osteophytes formation in T2DM patients with OA knee. Further longitudinal prospective studies are needed to explore the significance of these observations. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1176
Abstract 1928: Resistance of human melanoma to MART-1/HLA A2.1 specific CTL (F5 CTL)-killing: poor recognition, low MART-1 expression and reversal of resistance
Authors: Ali R. Jazirehi, Stavroula Baritaki, Benjamin Bonavida, James S. Economou
Journal: Cancer Research (2010)

Abstract Adoptive cell therapy (ACT) using ex vivo engineered autologous lymphocytes encoding high affinity TCRα/β genes specific for MART-1+/HLA-A2.1+ (F5 CTL) kill human melanoma lines in vitro in an MHC-I restricted and caspase-dependent manner and mediate modest clinical responses. Development of antigen-loss tumor variants is one mechanism of immune escape. The objective of this study is to investigate the mechanism of resistance to CTL-killing due to loss of recognition and reversal of resistance by pharmacological inhibitors. We hypothesized that the development of Ag-loss variants is due to degradation or epigenetic modifications of MART-1. Also, we hypothesized that aberrant apoptotic cell signaling contribute to immune resistance. To test the hypotheses, we generated F5 CTL-resistant clones (R) from sensitive parental (P) lines by growing the cells under F5 CTL selective pressure followed by limiting dilution. Detailed analysis revealed that compared to P cells, M244R clone exhibit significantly higher resistance to F5 CTL killing, proliferate at a higher rate, and are unable to trigger IFNγ release by F5 CTLs suggesting diminished MART-1 expression (loss of MART-1 was confirmed by gene analysis, surface HLA-A2.1 was unaltered). F5 CTLs recognized and interacted with MART-1 pulsed M244R clone (IFNγ secretion and conjugate formation), yet, the cells still remained resistant to F5 CTL killing. We observed deregulation and constitutive hyper-activation of the components of the NF-κB pathway leading to over-expression of anti-apoptotic Bcl-2, Mcl-1 and Bcl-xL in M244R clones. The proteasome inhibitor bortezomib efficiently blocked NF-κB activity, reduced the expression of resistant factors, restored recognition and sensitized the M244R clones to F5 CTL-induced killing. These novel results suggest that bortezomib, not only interferes with the deregulated signaling pathway but also restores recognition of low MART-1 expressing, poorly recognized immune resistant variants by F5 CTLs, thus, reverses the acquired resistance. These results also imply that immune resistance can not be solely explained by the development of MHC-/antigen-loss variants and is partly due to perturbed cell survival signaling pathways of the tumor cells. Targeted therapy with specific pharmacological inhibitors in conjunction with F5 CTL can override F5 CTL-resistance, which can improve clinical response. 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 1928.
Abstract 2499: Diagnostic serum biomarkers for canine hemangiosarcoma: a potential model of human angiosarcoma.
Authors: Eunju Choi, David Chen, Kim-Anh Lê Cao, Helle Bielefeldt-Ohmann, Caroline A. O'Leary, Michelle M. Hill
Journal: Cancer Research (2013)

Abstract People suffering from uncommon diseases often do not benefit from the advances in medical research due to lack of research. One such disease is angiosarcoma, a highly aggressive cancer originating from blood vessels with risk factors including toxic exposure, radiotherapy and lymphedema. Angiosarcoma in dogs (commonly called hemangiosarcoma) is a very similar disease with much higher prevalence, comprising up to 7% of all canine malignancies. For both species, an accurate diagnostic method is needed for more favorable outcome. We developed a biomarker discovery pipeline consisting of a high-throughput biomarker discovery platform and a database for data mining and statistical analysis for candidate identification. The platform screens for differential glycosylation of serum glycoproteins as potential biomarkers utilizing 20 individual lectins followed by direct coupling to tandem mass spectrometry. The database facilitates the identification of differential glycosylation and produces a ranked list of potential biomarker candidates. Using this pipeline, sera from 10 dogs with hemangiosarcoma with 10 age and sex-matched control sera were processed and analyzed. Candidates from the database were ranked based on its ability to classify normal and cancer. The ranked list of candidates for this screen composed of glycoproteins involved in cell migration, tumor immune response, and glycoproteins reported to be altered in human and canine angiosarcoma and other cancer types. Some examples will be shown to illustrate the change in specific glycosylation structures associated with cancer as measured by binding to specific lectin(s) while binding to other lectins are not changed. These glycosylation-specific changes are potentially more specific diagnostic biomarkers than circulating proteins alone. We are currently validating the identified candidates and pursuing the development of clinical tests to improve diagnosis and clinical outcomes of angiosarcoma for both dogs and humans. Citation Format: Eunju Choi, David Chen, Kim-Anh Lê Cao, Helle Bielefeldt-Ohmann, Caroline A. O'Leary, Michelle M. Hill. Diagnostic serum biomarkers for canine hemangiosarcoma: a potential model of human angiosarcoma. [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 2499. doi:10.1158/1538-7445.AM2013-2499
Serious complication following use of StomaphyX
Authors: J. Lenz, G. Hubens, P. Pelckmans, T. Moreels
Journal: Endoscopy (2011)

Roux-en-Y gastric bypass (RYGB) is a popular surgical procedure to treat morbid obesity [1]. StomaphyX (endoGastric Solutions Inc., Redmond, Washington, USA) is designed for incisionless transoral endoscopic plication and revision of the gastric pouch (EPRGP) in case of pouch dilation with weight gain [2] [3]. Nonresorbable polypropylene fasteners create full-thickness plications of the pouch wall, reducing its volume. StomaphyX was cleared by the Food and Drug Administration (FDA) in April 2007 [4] and clinical results are becoming available, with only 3 % early complications [5].
US approves "morning after" pill without prescription for women 15 years or older
Authors: M. McCarthy
Journal: BMJ (2013)

The US Food and Drug Administration has approved the use of one brand of a “morning after” emergency contraceptive without a prescription for women 15 years or older.

Previously, the FDA limited non-prescription sales of the drug, Plan B One-Step, to women aged 17 years or older. Those aged 16 or under could obtain the drug but only with a prescription.

Under the new FDA rules the product will also be available on shelves in store aisles where other family planning and women’s health products are displayed. Previously the product had to be kept behind pharmacy counters and not on open shelves.

The product …
Ectopic Production of the Isolated Alpha Subunit of the Glycoprotein Hormones
Authors: Saul W. Rosen, Bruce D. Weintraub
Journal: New England Journal of Medicine (1974)

Serum and tumor extract from a 27-year-old woman with metastatic gastric carcinoid contained high concentrations (20,000 ng per milliliter and 180,000 ng per gram) of a material ("alpha") resembling the alpha subunit of glycoprotein tropic hormones in immunologic, gel Chromatographic and biologic properties. Ectopic production of "alpha" was isolated and not accompanied by comparable amounts of a beta subunit or a complete glycoprotein hormone. The tumor also contained high concentrations of parathyroid hormone and calcitonin. Radioimmunoassay of serums from other patients with cancer (three of 24 patients with the carcinoid syndrome and three of 106 with bronchogenic carcinoma) revealed increased concentrations of "alpha" as compared to 106 controls without cancer. The alpha subunit of glycoprotein tropic hormones may be a quantitative marker of neoplasia in certain cases of cancer. (N Engl J Med 290:1441–1447, 1974)
A Case-Only Study of Vulnerability to Heat Wave–RelatedMortality in New York City (2000–2011)
Authors: Jaime Madrigano, Kazuhiko Ito, Sarah Johnson, Patrick L. Kinney, Thomas Matte
Journal: Environmental Health Perspectives (2015)

As a result of climate change, the frequency of extreme temperature events is expected to increase, and such events are associated with increased morbidity and mortality. Vulnerability patterns, and corresponding adaptation strategies, are most usefully conceptualized at a local level.We used a case-only analysis to examine subject and neighborhood characteristics that modified the association between heat waves and mortality. All deaths of New York City residents from 2000 through 2011 were included in this analysis. Meteorological data were obtained from the National Climatic Data Center. Modifying characteristics were obtained from the death record and geographic data sets.A total of 234,042 adult deaths occurred during the warm season of our study period. Compared with other warm-season days, deaths during heat waves were more likely to occur in black (non-Hispanic) individuals than other race/ethnicities [odds ratio (OR) = 1.08; 95% CI: 1.03, 1.12], more likely to occur at home than in institutions and hospital settings (OR = 1.11; 95% CI: 1.06, 1.16), and more likely among those living in census tracts that received greater public assistance (OR = 1.05; 95% CI: 1.01, 1.09). Finally, deaths during heat waves were more likely among residents in areas of the city with higher relative daytime summer surface temperature and less likely among residents living in areas with more green space.Mortality during heat waves varies widely within a city. Understanding which individuals and neighborhoods are most vulnerable can help guide local preparedness efforts.
EXTRACELLULAR REGULATORS OF GLIOBLASTOMA SIGNALING
Authors: J. J. Phillips, A. Wade, V. M. Tran, A. McKinney
Journal: Neuro-Oncology (2014)

BACKGROUND: Extracellular proteoglycans, including heparan sulfate proteoglycan (HSPG), play critical roles in the regulation of neural stem cell signaling and progenitor cell migration via their interactions with extracellular ligands, matrix, and cell receptors and may serve similar purposes in oncogenic states. In glioblastoma (GBM), our studies suggest that proteoglycans regulate critical oncogenic signaling pathways. Here we assess the function of proteoglycans and their alterations that drive GBM, and test the hypothesis that these may represent novel therapeutic targets and biomarkers of disease. METHODS: To investigate the role for proteoglycans in tumorigenesis we used a combination of primary human GBM, primary human GBM cultures, and a murine model for malignant glioma based on the genetic manipulation of neural progenitor cells. GAG structure was elucidated and quantified using liquid chromatography-mass spectrometry (LCMS), an ultra-sensitive and high-resolution technique that can overcome problems associated with low availability of biological samples. RESULTS: In GBM we identified patterns of altered expression of HSPG protein cores and their modifying enzymes relative to non-tumor brain, including the extracellular enzyme SULF2. Indeed, SULF2 is overexpressed in many human GBM and ablation of SULF2 function results in decreased activation of PDGFRα signaling and in decreased tumor growth in vivo. Consistent with a role for SULF2 in PDGFRA signaling in human GBM, SULF2 is upregulated in PDGFRA-amplified compared to non-amplified tumors (p < 0.05, n = 40 amplified, 332 non-amplified). SULF2 reduced HS sulfation, specifically the HS6S component of heparin, as determined by liquid chromatography-mass spectrometry (LCMS) and immunohistochemistry. As HS6S sulfation is an important determinant of HS-ligand binding, we investigated whether SULF2 could alter PDGF binding to HS. While ligand binding was similar, SULF2 was associated with altered expression and cell surface localization of PDGFRA. Thus, SULF2, and possibly HS6S, may regulate PDGFRA signaling via two distinct mechanisms. As HS structure is critical for normal neural stem cell proliferation and differentiation, we analyzed HS structure over tumor progression using LCMS. We demonstrate that tumor progression is associated with changes in GAG structure, and we are now using HS mimetics to try to inhibit the oncogenic role for proteoglycans in GBM. CONCLUSIONS: Our data demonstrate the functional importance of proteoglycans in GBM and suggest GAG structure may be particularly important for oncogenic signaling. While therapeutic targeting of single RTKs has been difficult in GBM, a drug targeting HS has the potential to simultaneously inhibit multiple oncogenic pathways in tumor cells and disrupt critical tumor-microenvironment interactions. SECONDARY CATEGORY: n/a.
Abstract 3432: p38 and Snail are critical for downregulation of E-cadherin during EMT in HNSCC
Authors: Maie St. John, Yuan Lin, Guanyu Wang, Jie Luo, Douglas Sidell, Miranda Dennis, Jagmeet Mundi, Elliot Abemayor, Steven Dubinett
Journal: Cancer Research (2011)

Abstract Objectives: To determine the roles of Snail and p38 in the inflammation-induced promotion of EMT in HNSCC. Study Design: A molecular biology study. Real-time quantitative RT-PCR, Western blot analysis, spheroid modeling, and immunohistochemical staining of human HNSCC tissue sections were used to determine how inflammation affects Snail and p38. Setting: An academic hospital laboratory. Subjects and Methods: Relative RNA levels were determined by RT-PCR, and protein expression was evaluated by immunofluorescence (IF) and in situ by immunohistochemical staining of human HNSCC tissue sections. Results: p38 kinase inhibitor treated, and p38 shRNA HNSCC cell lines demonstrated a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of the transcriptional repressor Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. An inverse relationship between p38 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections. p38 is required for the robust IL-1β induced E-cadherin downregulation and Snail upregulation. IL-1β increases p-p38 and has a more rapid and robust effect on p38 in Snail overexpressing cell lines. Conclusions: In gastrulation, it is a Snail-independent pathway in which p38 is required in the primitive streak to downregulate E-cadherin expression at the posttranscriptional level. Herein we provide the first report that p38 is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC. A Snail-p38 feedback loop jointly down regulates E-cadherin and drives a potent EMT in HNSCC. This newly defined pathway has important implications for targeted chemoprevention and therapy. 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 3432. doi:10.1158/1538-7445.AM2011-3432
PTH-040 What is the Utility of Capsule Endoscopy in Patients with Obscure Gastrointestinal Bleeding and Chronic Renal Failure?
Authors: P S Sidhu, M E McAlindon, R Sidhu
Journal: Gut (2013)

<h3>Introduction</h3> Anaemia is a common complication of chronic renal failure (CRF). The cause of the anaemia is often multifactorial including erythropoietin deficiency, uraemic platelet dysfunction, absolute iron deficiency anaemia (IDA) and overt bleeding (OB). Capsule endoscopy (CE) has developed an important role in the investigative pathway of obscure gastrointestinal bleeding (OGB). We conducted a study to evaluate the utility of CE in such patients after negative bidirectional endoscopies and their subsequent management consequences. <h3>Methods</h3> We retrospectively reviewed our data set and isolated patients with OGB and CRF. This data set was scrutinised to elucidate demographics, factors that increase yield and their subsequent management. <h3>Results</h3> Of the 1324 patients investigated, 4.1%(n = 54) had CRF. The mean age was 68 years (range = 37–86) and males consisted of 56% of the new cohort (n = 33). The indications for CE was IDA in 61%(n = 33) of patients and OB in the remaining 39%. The majority 89%(n = 48) of patients had significant other co-morbidity which included cardiovascular (13), diabetes (10), haematological (8), cancers (7), respiratory disease (7) and chronic liver disease (3). 3 patients were on warfarin and 4 patients were transfusion dependent. The diagnostic yield (as defined by lesions responsible for OGB) identified on CE was 48%(n = 26). Angioectasia was the commonest diagnosis identified in 33% of patients (n = 18). Other findings were ulcers and erosions 22%(n = 12), fresh blood without a definite bleeding site 17%(n = 9), strictures in 7%(n = 4), whilst crohns and polyps were seen in 2%(n = 1) each respectively. CE identified significant lesions within the upper gastrointestinal tract in 19%(n = 10) of patients. There was no significant difference in the diagnostic yield between those with IDA and OB (p = 0.53) and between the sexes (p = 0.76). Management was altered in 44%(n = 24) of those with a positive yield, in the form of further procedures (48%, n = 12). These procedures included push-enteroscopies 58%(n = 7), double balloon enteroscopies 25%(n = 3) and 3 OGDs. In the same group, argon photocoagulation therapy was applied to 83%(n = 10) of patients. <h3>Conclusion</h3> CE has a high diagnostic yield in patients with CRF with a positive outcome on subsequent management. Small bowel angioectasia is the commonest finding. CE should be considered in the work up of patients with CRF and OGB. <h3>Disclosure of Interest</h3> None Declared.