tbuckley/cabot-search huggingface dataset:
Abstract 186: Methyl binding domain protien 2 (MBD2) promotes epithelial dedifferentiation in breast cancer
Authors: Omar Mian, Gordon Ginder
Journal: Cancer Research (2010)

Abstract Purpose: Methyl-CpG Binding Proteins (MCBPs) are thought to function as the interpreters of epigenetic information encoded in cytosine methylation. Their ability to translate DNA methylation into local transcriptional repression has sparked interest in the role MCBPs play in cancer. We have studied the function of Methyl-Binding Domain Proteins (MBDs) in human mammary epithelial cancers, where repatterning of CpG methylation is common. Results: We find Methyl Binding Domain Protein 2 (MBD2) promotes the abnormal multi-cellular morphology characteristic of tumor cells. Stable MBD2 knockdown in MCF7 cells leads to an increased proportion of differentiated epithelial structures (e.g. acinii, 70%, [CI=0.55-0.83]) in 3D culture when compared to untransfected (46%, [CI=0.39-0.53], p ≤ 0.038) or control shRNA transfected (37%, [CI=0.29-0.45], p ≤ 0.012) populations. To identify the genes underlying this MBD2 dependant phenotype, high throughput quantitative PCR data were probed using self organizing map (SOM) analysis. We found only a small subset of the breast cancer specific tumor suppressors known to be silenced by promoter hypermethylation were regulated by MBD2 alone (n=7, 15%). Several genes previously shown (by us and others) to be MBD2 bound by chromatin immunoprecipitation (ChIP) were not induced by MBD2 knockdown, suggesting MBD2 exhibits tumor and tissue-type specificity. Moreover, gene sets activated by the DNA methylation inhibitor, 2-deoxy-5-aza-cytidine (4uM, n=30, 67%), and MBD2 knockdown (n=18, 40%) were different, suggesting pleiotropic activity; for example at loci that exhibit additive induction (n=11, 24%) and those that do not. MBD2 dependant genes were rapidly re-suppressed upon rescue with a shRNA binding site variant MBD2 and ChIP studies confirmed binding of MBD2 at all genes examined within the MBD2 dependant cluster. Transient siRNA mediated knockdown of individual MBD2 dependant genes did not restore the dedifferentiated phenotype, suggesting coordinate regulation by multiple downstream targets of MBD2. Conclusion: Our studies show MBD2 promotes tumor suppressor silencing and dedifferentiation in breast cancer and intimate a role for MBD2 in fine-tuning mammary epithelial gene expression patterns. 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 186.
A7.19 Systemic inhibition of MIR-148A by antagomirs reduces CD4<sup>+</sup>T helper cell numbers and alleviates inflammation in a preclinical model of transfer colitis
Authors: P Maschmeyer, J Zimmermann, CL Tran, C Haftmann, B Rausch, R Riedel, S Herzog, HD Chang, A Radbruch, MF Mashreghi
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> T helper type 1 (Th1) cells are involved in rheumatic diseases such as Crohn´s disease or rheumatoid arthritis and have a history of chronic autoantigenic stimulation. We have shown that Th1 cells adapt to chronic inflammation by upregulating the expression of the microRNA (miR)-148a. MiR-148a promotes the survival of chronically activated Th1 cells by regulating the expression of the proapoptotic protein Bim. Thus, we tested the suitability of miR-148a as a therapeutic target for the selective elimination of proinflammatory Th1 cells in a preclinical model of colitis. <h3>Methods</h3> Chronically activated Th1 cells were transferred into Rag1-deficient mice to induce colitis. Then, mice were intravenously injected with antagomirs that specifically target the microRNA-148a (antagomir-148a) or with control antagomirs (antagomir-scr). For assessing the function of T cell-intrinsic expression of miR-148a in colitis, we transduced Th1 cells with inducible microRNA sponges prior to transfer into Rag1-deficient mice. Colitic inflammation was determined by the weight-to-length ratios of colons. Colonic Th cells were sorted by FACS to measure miR-148a expression by qRT-PCR. The expression of Bim and Bcl-2 as well as numbers of viable Th1 cells, were determined by flow cytometry. <h3>Results</h3> Systemic inhibition of miR-148a by antagomirs alleviated colitis in mice as measured by reduced weight-to-length ratios of their colons. The numbers of viable Th1 cells were reduced up to 50% in mice that were treated with antagomir-148a when compared to mice that were injected with antagomir-scr. Antagomir-148a injections were efficient and resulted in a 30% reduction of miR-148a in colonic Th1 cells. The expression of the proapoptotic protein Bim was increased up to 30% in Th cells from antagomir-148a treated mice, while the anti-apoptotic protein Bcl-2 was unchanged. Th cell specific inhibition of miR-148a by miR-sponges during colitis led to a 30% reduction of Th cells in the colons of colitic mice and reduced the weight-to-length ratio. <h3>Conclusions</h3> We suggest that miR-148a controls the survival of proinflammatory Th1 cells in chronic inflammation by inhibiting Bim expression in a Th cell intrinsic fashion. Thus, miR-148a might represent a suitable target for the selective depletion of proinflammatory Th1 cells in chronic inflammation.
Gangrenous Leg in a Patient With Diabetes on MDP Bone Scintigraphy
Authors: Osayande Evbuomwan, Olusegun Akinwale Ayeni, Shireen Dhoodhat, Mboyo Di Tamba Vangu
Journal: Clinical Nuclear Medicine (2016)

Diabetic patients with peripheral arterial disease frequently experience gangrene of the lower limbs. It has been suggested that a bone scan is useful in differentiating viable from nonviable tissues in patients with extensive peripheral gangrene and thus can help determine the appropriate level of amputation in such patients. We present a 68-year-old diabetic woman with right breast cancer, who was referred to our facility for a bone scan as part of her metastatic workup. Bone scan findings revealed absolute photon deficiency in the distal half of her left lower limb.
PC0001 Effectiveness of diclofenac versus acetaminophen in primary care patients with knee osteoarthritis: A randomized clinical trial
Authors: S.P. Verkleij, P.A. Luisterburg, B.W. Koes, A.M. Bohnen, S.M. Bierma-Zeinstra
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Guidelines recommend acetaminophen as medication of first choice when pain medication is needed. In clinical practice, however, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as first prescribed medication. <h3>Objectives</h3> We assessed the effectiveness of diclofenac versus acetaminophen in patients with mild knee osteoarthritis (OA) who consulted their GP. <h3>Methods</h3> This pragmatic open-label randomized controlled trial, with a 12-weeks follow-up period [1], included 104 patients aged 45 years and older, and fulfilled the clinical American College of Rheumatology (ACR) criteria for knee OA. Patients were randomly allocated to diclofenac (n=52) (maximum daily dose of 150 mg.) or acetaminophen (n=52) (maximum daily dose of 3000 mg.) for max 4-weeks. Primary outcomes were daily knee pain severity measured with an 11-point numeric rating scale (NRS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) collected with questionnaires at 3, 6, 9, and 12 weeks follow-up and daily knee pain (NRS) collected with a diary (for 4 weeks). Secondary outcome was daily medication intake. Generalized estimated equations analyses were adjusted for age, gender, and baseline pain differences. <h3>Results</h3> At 12-weeks follow-up, NRS knee pain (β: -0.1; 95% CI: -0.9 to 0.7) and KOOS knee pain (β: -0.3; 95% CI: -7.0 to 6.4) did not differ between the groups (see figure). At 4-weeks follow-up (the end of treatment period), no differences were found regarding daily NRS knee pain and medication intake. <h3>Conclusions</h3> At 4 and 12 weeks follow-up, there were no differences between the two treatment groups, diclofenac and acetaminophen, in reducing knee pain in patients with knee OA in primary care setting. These results endorse the recommendation of acetaminophen as "first choice medication" in (inter)national guidelines regarding primary care patients with knee OA. <h3>References</h3> Verkleij SPJ, Luijsterburg PAJ, Koes BW, Bohnen AM, Bierma-Zeinstra SMA. Effectiveness of diclofenac versus acetaminophen in primary care patients with knee osteoarthritis: [NTR1485], DIPA-trial: design of a randomized clinical trial. BMC Musculoskelet Disord. 2010;11:7. <h3>Disclosure of Interest</h3> None Declared
Abstract 335: Therapeutic targeting of EphB4 with a novel monoclonal antibody
Authors: Whitney A. Spannuth, V. Krasnoperov, R. Liu, Alpa M. Nick, Yvonne G. Lin, William Merritt, Robert L. Coleman, Parkash S. Gill, Anil K. Sood
Journal: Cancer Research (2010)

Abstract Objective: EphB4 is a transmembrane receptor tyrosine kinase that plays an important role in neural plasticity and angiogenesis. Its biological and clinical relevance in ovarian cancer is the focus of this study. Methods: Benign ovarian (ML5 and ML10) and ovarian cancer (Hey, SKOV3ip1, A2780-par, A2780-cp20, and IGROV-af1) cell lines, 7 normal ovarian and 85 invasive ovarian cancer samples were evaluated for EphB4 expression by Western blot or immunohistochemistry. Univariate and multivariate analyses were performed for clinical correlation. EphB4 blockade was accomplished using a novel EphB4-targeted monoclonal antibody (EphB4-131). Systemic delivery of EphB4-131 antibody was utilized in vivo to target EphB4 in orthotopic mouse models of ovarian cancer. Results: By Western blot analysis, all five malignant cell lines overexpressed EphB4, whereas the two benign cell lines had low EphB4 expression. All of the normal ovarian tissues had low or absent EphB4 expression. Among the invasive ovarian carcinomas (mean age of patients was 59.4 years), 73 (86%) had some level of EphB4 expression and overexpression (moderate or strong) was noted in 58% of all samples. EphB4 overexpression significantly correlated with advanced stage (III or IV; p&amp;lt;0.001) and presence of ascites (p&amp;lt;0.001). In multivariate analysis, EphB4 overexpression (p=0.04) and stage (p=0.03) were independent predictors of poor survival. EphB4-131 antibody led to decreased EphB4 expression in A2780-cp20 and IGROV-af1 cell lines, lasting for over 5 days. Compared to controls, EphB4-131 antibody alone significantly decreased tumor growth in A2780-cp20 (83%, p&amp;lt;0.01) and IGROV-af1 (80%, p&amp;lt;0.001) orthotopic ovarian cancer models. Combination therapy with EphB4-131 antibody and docetaxel resulted in the greatest tumor reduction in both A2780-cp20 and IGROV-af1 cell lines (94-98% reduction versus controls; p&amp;lt;0.01). Conclusions: EphB4 overexpression is predictive of poor clinical outcome in ovarian cancer patients and is associated with aggressive features. Therapeutic targeting of EphB4 with the novel antibody EphB4-131 is an attractive strategy for further development. 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 335.
536 SHORT-TERM SURVIVAL IN PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS TREATED WITH PENTOXIFYLLINE vs. CORTICOSTEROID: A NON-INFERIORITY TRIAL – A PRELIMINARY REPORT
Authors: D.J. Kim, K.T. Suk, S.H. Park, W.Y. Tak, H.J. Yim, S.H. Um, K.T. Yoon, Y.S. Kim, H.J. Lee, S.K. Baik, J.S. Lee, I.H. Kim, H.S. Kim, J.H. Sohn
Journal: Journal of Hepatology (2013)
SAT0227 Low Diagnostic Utility Of Candidate Definitions for a Positive MRi of the Spine in Axial Spondyloarthritis
Authors: U. Weber, V. Zubler, Z. Zhao, R. G. Lambert, K. Rufibach, S. M. Chan, S. J. Pedersen, M. Ostergaard, W. P. Maksymowych
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> A recent consensus statement based on a systematic literature review by the Assessment of SpondyloArthritis International Society suggested the presence of ≥3 corner inflammatory lesions (CIL) or of several corner fat lesions (CFL) as candidate definitions for a positive MRI of the spine in axial spondyloarthritis (SpA) [1]. <h3>Objectives</h3> To determine data-driven cut-off values for spinal CIL and CFL yielding a specificity ≥90% and to evaluate their diagnostic utility in non-radiographic axial SpA (nr-axSpA) and ankylosing spondylitis (AS). <h3>Methods</h3> The study sample comprised 2 independent cohorts A/B of 130 consecutive patients with back pain ≤50 years newly referred to 2 university clinics, and 20 healthy controls, in whom MRI scans of the entire spine were available. Patients were classified according to clinical examination and pelvic radiography as having nr-axSpA (n=50), AS (n=33), or non-specific back pain (NSBP; n=47). Spinal MRI were assessed by 4 blinded readers according to the standardized CanDen modules. Readers recorded bone marrow edema and fat infiltration in the central and lateral/posterior compartment of all 23 discovertebral units. We calculated cut-off values for CIL and CFL to obtain ≥90% specificity and the corresponding area under the curve (AUC) with confidence interval (CI). Finally, we tested the diagnostic utility (mean sensitivity/specificity of 4 readers) of cut-off values for spinal MRI as proposed in the literature (≥3 CIL [1] and ≥5 CFL [2]) for nr-axSpA and AS patients in both cohorts. <h3>Results</h3> For cohorts A/B, the rounded lesion cut-offs to obtain ≥90% specificity were 3/2 CIL and 7/10 CFL, respectively. The corresponding AUC for CIL were 0.69 (CI 0.49-0.84) and 0.69 (CI 0.47-0.85) in the 2 cohorts, and for CFL 0.60 (CI 0.43-0.75) and 0.71 (CI 0.56-0.82), respectively. The diagnostic utility of the spinal thresholds of ≥3 CIL and of ≥5 CFL was low in both cohorts when comparing nr-ax SpA versus NSBP. Diagnostic utility of 2 candidate definitions of a positive MRI of the spine in cohorts A/B <h3>Conclusions</h3> In this controlled study, the definitions of a positive spinal MRI proposed in a recent consensus statement showed low diagnostic utility in nr-axSpA. While a cut-off of ≥2/≥3 CIL for a positive MRI was optimal, the threshold for CFL was as high as 10. <h3>References</h3> Hermann KG et al. ARD 2012;71:1278. [2] Bennett A et al. ARD 2010;69:891. <h3>Disclosure of Interest</h3> None Declared
MS2-1: Early Life Exposures and Breast Cancer Risk: Preeclampsia and Puberty.
Authors: MR Forman
Journal: Cancer Research (2011)

Abstract Women diagnosed with preeclampsia (PE) in pregnancy have a 12–72% reduced risk of breast cancer compared to women with a normotensive pregnancy while her daughter from the index pregnancy also has a lower breast cancer risk than normotensive (NT) daughters. Why is this so? The preeclamptic (PE) pregnancy is highly androgenic with low levels of estrogens and insulin-like growth factor −1 levels. We followed a cohort of offspring of preeclamptic pregnancies and of normotensive pregnancies from birth through 12.8 years to examine whether daughters of the PE pregnancy would delay breast development, have lower estrogens and IGF-1 levels in puberty compared to their normotensive offspring and also compared factors influencing age at onset of puberty in the PE and NT girls. In young pubertal aged girls of 10 years, high dehydroepiandosterone- sulfate levels (DHEAS) but low testosterone levels may reflect the in utero exposures of the PE compared to the NT offspring. By 13 years, PE daughters had a 20% lower risk of breast development (OR= 0.80 95% CI 0.70−1.00). In an examination of the role of early life exposures on age at onset of puberty, we report that age of greatest weight gain in infancy is earlier for the NT (3-6 months) than the PE (6-12 months) and that age of greatest weight gain in infancy is associated with the odds of age at onset of puberty. Our findings and those of others in early life exposures and breast cancer risk provide clues to tailoring the effect of early exposures by maternal morbidity in pregnancy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS2-1.
Abstract 325: Splice isoform switching: A new mechanism controlling EMT and breast cancer progression
Authors: Rhonda L. Brown, Lauren M. Reinke, Marin S. Damerow, Denise Perez, Lewis A. Chodosh, Jing Yang, Chonghui Cheng
Journal: Cancer Research (2012)

Abstract Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis. When abnormally activated, EMT promotes cancer metastasis and recurrence. Here we show that splice isoform switching constitutes a novel mechanism that controls EMT. We identified a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s, which is regulated at the level of alternative splicing, is essential for cells to undergo EMT and is required for the formation of breast tumors that display EMT characteristics in mice. We demonstrate that the splicing factor ESRP1 controls the CD44 isoform switch and is critical for regulating the EMT phenotype. Furthermore, the CD44s isoform activates Akt signaling and inhibits cell death, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression is upregulated in high-grade human breast tumors and correlates with the level of the mesenchymal marker N-cadherin in these tumors. Together, these data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression. 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 325. doi:1538-7445.AM2012-325
Primary eosinophilic colitis as an unusual cause of chronic diarrhea
Authors: C. Lee, H. Kim
Journal: Endoscopy (2010)

A 50-year-old woman presented with a 1-year history of watery diarrhea and gradual weight loss. One week before admission, the frequency of watery diarrhea increased up to six times per day, accompanied by hematochezia and lower abdominal pain. The patient denied any prior history of systemic disease or medications. Laboratory evaluation revealed normal leukocyte count (8.7 × 109/L [normal 4.0 – 10.8 × 109/L]) with marked peripheral blood eosinophilia (15 %). Multiple stool tests were negative for bacterial or parasitic infections, and no evidence of malignancy or other systemic disease was noted during the comprehensive work-up. Colonoscopy revealed patchy subepithelial hemorrhages, friability, submucosal edema, and loss of vascularity in the transverse colon and left colon ([Fig. 1]). Multiple biopsies were obtained throughout the involved colonic segments and normal-appearing colonic segments. They showed heavy infiltration of tissue eosinophils with more than 30 per high-power field in the lamina propria, highly suggestive of eosinophilic colitis ([Fig. 2]). The patient was diagnosed with primary eosinophilic colitis and was treated with oral prednisolone (1 mg/kg per day). Her symptoms resolved greatly within 5 days and the blood eosinophil count normalized within 2 weeks. With improvement of symptoms, prednisolone treatment was tapered slowly over the next 3 months. Follow-up endoscopy 2 months later showed marked improvement of the colonic inflammation ([Fig. 3]). The patient has remained well without recurrence of symptoms during the 12 months of follow-up.
Abstract 2025: Let-7 family miRNAs regulate estrogen signaling pathways mediated by ER alpha-66 and ER alpha-36 in breast cancer
Authors: Yingchun Zhao, Caishu Deng, Jiarui Wang, Jing Xiao, Hongwei Zhang, Zoran Gatalica, Robert Recker, Gary G. Xiao
Journal: Cancer Research (2010)

Abstract To understand how microRNAs (miRNAs) regulate breast cancer tumorigenesis, a miRNA expression microarray screening was performed using RNAs from formalin-fixed paraffin-embedded (FFPE) breast tissues, which included benign (n=13), ductal carcinoma in situ (DCIS) (n=16), and invasive ductal carcinoma (IDC) (n=15). Twenty miRNAs that were differentially expressed (p&amp;lt;0.01) were identified, of which let-7 family miRNAs were down-regulated in human breast cancer tissues at stages of DCIS and IDC compared to benign stage. To understand the role of let-7 miRNAs further, we performed bioinformatics analysis and found that let-7 miRNA sequences match sequences in the 3’-UTRs of estrogen receptor alpha 66 (ER-α66) and another novel receptor ER-α36. The targeting of let-7 miRNAs on ER-α66 and ER-α36 was further confirmed by a number of experimental assays, including luciferase assay, protein expression, and mRNA expression. Overexpression of let-7 miRNAs in ER-α66-positive breast cancer MCF7 cell line negatively affected ER-α66 mediated genomic estrogen pathway. As expected, down-regulation of the ER-α66 signaling by let-7 miRNAs inhibited cell proliferation, and subsequently triggered the cell apoptotic process in MCF7 cells. On the other hand, overexpression of let-7 miRNAs in ER-α66-negative cell line MB-MDA-231 negatively affected ER-α36 mediated non-genomic estrogen pathway. Besides, down-regulation of let-7 is correlated with up-regulation of ER-α36 in tamoxifen (Tam) and ICI-182780 (ICI) resistance in MCF7 cell line. Forced overexpression in Tam-and ICI-resistant MCF7 cells dampened ER-α36 expression. In conclusion, our findings not only indicate a new regulatory mechanism of let-7 miRNAs in ER mediated cellular malignant growth of breast cancer, and but also provide potential biomarkers and/or surrogate therapeutic targets useful for early diagnosis and/or therapeutic options for breast cancer. 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 2025.
Development of a Model of Chronic Lymphocytic Leukemia in Inbred Strain 2 Guinea Pigs&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: M E Key, J S Brandhorst, C D Bucana, M G Hanna
Journal: JNCI Journal of the National Cancer Institute (1983)

A new transplantable leukemia (KSL) of unknown etiology that arose in a female Sewall-Wright strain 2 guinea pig is described. KSL cells morphologically resembled medium to large lymphocytes, displayed surface la antigen and receptors for complement and fOr the Fc portion of immunoglobulin, and synthesized surface immunoglobulin (lgM), These characteristics suggest a leukemia of Blymphocyte origin, KSL cells were shown to be sensitive in vivo to both cycloPhosphamide and 1 ,3-bis(2-chloroethyl}-1-nitrosourea; however, neither drug effectively prevented eventual recurrence of the disease, KSL leukemia was also shown to be distinct from another guinea pig lymphatic leukemia (L2 C) with respect to cell morphology, antigeniCity, and in vivo growth rate, In this last respect, KSL appeared more closely related to the chronic lymphocytic leukemias, Thus KSL is the first chronic lymphocytic leukemia in the guinea pig to be characterized; it is also the only guinea pig model of lymphatic leukemia that is distinct from l2C leukemia currently available for, study.