tbuckley/cabot-search huggingface dataset:
Abstract 4090: RASSF1A gene specific methylation by overexpression of miR-200c in lung cancer
Authors: Sung-Min Chun, Min-Young Jin, Jene Choi, Je-Hwan Lee, Jung Jin Hwang, Chung-Soo Kim, Se Jin Jang
Journal: Cancer Research (2010)

Abstract DNA methylation, which is an important epigenetic mechanism of gene regulation during cellular differentiation, is mediated by enzymatic actions of DNA methyl transferase family (DNMT). In pathologic conditions, however, certain critical genes such as tumor suppressor genes of various human cancers are aberrantly methylated resulting in inactivation of the genes regardless of DNMT amount. In this process, what induces aberrant methylation of a specific gene is currently unknown. We focused actions of microRNA because of their natural function of sequence recognition. As a model, we selected miR-200c and RASSF1A since those are frequently overexpressed and hypermethylated in lung cancer, respectively, and have partial sequence homology between miR-200c and promoter region of RASSF1A. In this study, we tested expression of miR-17, 21, 200c and 205 by quantitative real-time PCR and methylation status of RASSF1A, CDH13, p16ink4a, DAPK1, and APC1 by pyrosequencing assay in 3 lung cancer cell lines and 10 fresh frozen normal and tumor lung tissues. Fluorescent In Situ Hybridization (FISH) using anti-miR-200c probe labeled with Cy-3 dye was performed to confirm expression and localization of mature miR-200c. Interestingly, we found A549 and H460 cells were completely hypermethylated in RASSF1A promoter region and showed high level of miR-200c expression. In contrast, Calu6 cells showed opposite results. In vitro inhibition of miR-200c by transfection of anti-miR-200c oligonucleotide induced gradual decrease in methylation level of RASSF1A in A549 and H460 cells without change in expression of DNMT. Decrease of CpG methylation by anti-miR-200c transfection was associated with increase of RASSF1A gene expression in A549 and H460 cells. Calu6 cell showed no change in methylation level of RASSF1A. This effect was not seen in anti-miR-17 transfected cells. Transfection of anti-miR-200c did not affect methylation level of other frequently hypermethylated genes including CDH13, p16ink4a, DAPK1, and APC1. The results suggest that overexpression of miR-200c induces sequence specific methylation of RASSF1A and provide a clue to gene specific reactivation of epigenetically silenced genes. (This work was supported by the Korea Research Foundation Grant funded by the Korean Government. [KRF-2008-357-E00006], This study was supported by a grant of the Korea Health 21 R&amp;D Project, Ministry of Health &amp; Welfare, Republic of Korea. (A062254)) 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 4090.
CD34 Splice Variant: An Attractive Marker for Selection of Gene-Modified Cells
Authors: Boris Fehse, Anke Richters, Kira Putimtseva-Scharf, Hannes Klump, Zhixiong Li, Wolfram Ostertag, Axel R. Zander, Christopher Baum
Journal: Molecular Therapy (2000)

This study presents a promising selection system for gene-modified cells other than human hematopoietic progenitor and endothelial cells based on transgenic expression of human CD34. Three retrovirally transduced variants of CD34 were compared, differing in the length of their cytoplasmic domains. These were the full-length transmembrane protein (flCD34), a truncated form (tCD34) that is found as a naturally occurring splice variant and has a partial deletion of the cytoplasmic domain for signal transduction, and an engineered variant which is completely deprived of its cytoplasmic tail (dCD34). All three variants allowed selection of gene-modified cells using commercially available immunoaffinity technology. However, examination by flow cytometry as well as by Southern, Northern, and Western blot revealed that dCD34, as opposed to tCD34, is not stably anchored in the membrane and thus is expressed at low levels on the surface of transduced cells. Therefore, tCD34 was chosen as the more promising candidate for a clinically applicable cell surface marker. We show that gene-modified human primary T lymphocytes expressing tCD34 can be enriched to high purity (>95%) using clinically approved immunoaffinity columns. In addition, we demonstrate the utility of tCD34 for surface marking of murine hematopoietic cells in vivo, including primary T lymphocytes detected 9 weeks after bone marrow transplantation. This study presents a promising selection system for gene-modified cells other than human hematopoietic progenitor and endothelial cells based on transgenic expression of human CD34. Three retrovirally transduced variants of CD34 were compared, differing in the length of their cytoplasmic domains. These were the full-length transmembrane protein (flCD34), a truncated form (tCD34) that is found as a naturally occurring splice variant and has a partial deletion of the cytoplasmic domain for signal transduction, and an engineered variant which is completely deprived of its cytoplasmic tail (dCD34). All three variants allowed selection of gene-modified cells using commercially available immunoaffinity technology. However, examination by flow cytometry as well as by Southern, Northern, and Western blot revealed that dCD34, as opposed to tCD34, is not stably anchored in the membrane and thus is expressed at low levels on the surface of transduced cells. Therefore, tCD34 was chosen as the more promising candidate for a clinically applicable cell surface marker. We show that gene-modified human primary T lymphocytes expressing tCD34 can be enriched to high purity (>95%) using clinically approved immunoaffinity columns. In addition, we demonstrate the utility of tCD34 for surface marking of murine hematopoietic cells in vivo, including primary T lymphocytes detected 9 weeks after bone marrow transplantation.
Abstract 4868: Interaction between DNMT3B and polycomb repression complexes and their role in histone modification
Authors: Yajun Li, Beth O. Van Emburgh, Bilian Jin, Keith D. Robertson
Journal: Cancer Research (2010)

Abstract Epigenetic modifications, such as DNA methylation and the histone code, play crucial roles in regulating gene expression during development. Aberrant DNA methylation patterns, characterized by global genomic hypomethylation and gene specific hypermethylation at CpG islands, are found in all cancer cells and contribute directly to tumor development. DNA methyltransferases are responsible for the de novo or heritable maintenance of DNA methylation. DNMT3A and DNMT3B de novo methyltransferases contribute largely to the methylation of retrotransposon sequences and satellite repeats in pericentromeric regions. It is still unclear how gene-specific epigenetic modification patterns are established and maintained in cancer cells. Recently, high-throughput studies reported an overlapping distribution of polycomb repression complexes regulating histone modifications and DNA methyltransferase mediated DNA methylation, suggesting that there are interactions among these epigenetic regulators. Our previous data from DNA methyltransferase knock out cell lines revealed that epigenetic modifiers and the histone code influence the propensity of a gene to become hypermethylated in cancer and that DNMT3B plays an important role in regulating PRC1 function. To gain insight into the mechanisms of how DNMT3B/DNA methylation effects the histone code, and vice versa, we studied the protein-protein interactions between PRC1 components and DNA methyltransferase 3B and their functional consequences. We expressed DNMT3B and each PRC component in both baculovirus and E. coli expression systems. Pull down assays showed that there were multiple interactions between PRC1 components (eg. CBX4 /hPc2) and DNMT3B. Protein-protein interaction domains were further mapped. We then used an in vitro ubiquitination system to study the role of DNMT3B in histone H2A ubiquitination and also studied the effects of these interactions on gene expression in human tumor cell lines. Our results suggest that the interplay between DNMT3B/DNA methylation and PRC1 is important for the function of each protein/complex and that aberrations in these interactions contribute to epigenetic dysregulation in cancer cells. (Supported by NCI grant R01CA114229) 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 4868.
Abstract P6-05-05: Triple receptor comparison between primary breast cancer and metachronous or synchronous liver metastasis
Authors: S Tuyls, O Brouckaert, A Vanderstichele, J Vanderhaegen, F Amant, K Leunen, A Smeets, P Berteloot, E Van Limbergen, C Weltens, S Peeters, D Vanbeckevoort, G Floris, P Moerman, R Paridaens, H Wildiers, I Vergote, M-R Christiaens, P Neven
Journal: Cancer Research (2012)

Abstract Background: Decisions about systemic treatment in women with metastatic breast cancer are currently based on the presence of estrogen receptors (ER), progesterone receptors (PR) or Human Epidermal growth factor Receptor 2 (HER2 receptors) in the primary tumor. Recently, several studies have reported significant discordances in ER, PR and HER2 status between the primary tumor and metastatic lesions and this may vary by metastatic site. Prognostic implications remain unclear although alterations in ER, PR and/or HER2 can influence metastatic management. This study represents one of the largest studies evaluating how frequent receptor discordances occur in liver metastasis, whether this alters therapeutic options and impacts prognosis. Patients and methods: 246 breast cancer patients with histological confirmed liver metastasis were analyzed in this retrospective study. Immunohistochemistry (IHC) and/or FISH were used to determine ER, PR and HER2 receptor status. We excluded patients when comparison between receptors of primary tumor and metastasis was impossible due to missing data (n = 85), when liver metastasis did not originate from breast cancer (n = 36) and when pathology was obtained from autopsy specimens (n = 38). Results: 87 patients had matched tissue samples of primary tumor and liver metastasis with possible comparison of at least one of the receptors. Table 1 summarizes changes in ER, PR, HER2 between primary and metastatic lesion. Discordance in receptor status was associated with shorter time to death (63.3 months) compared to the concordant group (75.5 months). Conclusions: A significant proportion of ER and PR show discordance between primary tumor and liver metastasis. However we could not establish the same level of discordance for the HER2 receptors as in other studies. In general, only about 1 in 5 patients gained new (endocrine or targeted) therapeutic options. Tissue confirmation remains important to evaluate whether metastatic disease has become endocrine insensitive (in approximately 1 in 5 patients), avoiding unnecessary delay in chemotherapy. Discordance in receptors may be associated with inferior prognosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-05.
FRI0233 Classification of 156 japanese patients with anca-associated vasculitides by using the european medicines agency algorism with the addition of surrogate markers for pulmonary vasculitis
Authors: M. Yamamura, K.-E. Sada, T. Fujii, M. Harigai, Y. Arimura, H. Makino
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), Churg-Srauss syndrome (CSS) and microscopic polyangiitis (MPA) constitute the ant-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), but disease evolution, organ involvement and prognosis differ substantially between them. A previous study suggests the predominance of MPA in Japanese AAV patients<sup>1)</sup>, the survey was limited to the local geographical territories. <h3>Objectives</h3> To further determine the epidemiological feature of Japanese patients with AAV. <h3>Methods</h3> The RemIT-JAV study, a prospective cohort study, has been undertaken to clarify the effectiveness and safety of the initial remission induction therapy employed for Japanese patients with AAV. 156 patients enrolled in the study were classified according to the European Medicines Agency (EMEA) algorithm with the addition of surrogate markers for pulmonary vasculitis. <h3>Results</h3> Based on the EMSA classification algorism for AAV, 17 patients (female/male=12/5; mean ± SEM=58±16 years old) were classified as having CSS, 34 patients (22/12; 63±12 years old) were GPA, and 94 patients (54/40; 70±10 years old) were MPA. By applying surrogate markers for pulmonary vasculitis, 16 unclassifiable patients could be classified into the pulmonary limited type of MPA. 9 patients with CSS were positive for MPO-ANCA (53%); 15 patients with GPA were positive for MPO-ANCA (44%), while 19 patients positive for PR3-ANCA; and 92 patients were positive for MPO-ANCA with only 2 patients being positive for PR3-ANCA. In CSS patients, skin and neurologic manifestations were more common (77% and 94%, respectively), followed by ENT, lung/air way, and renal diseases (ca. 30%). Both GPA and MPA patients often presented with constitutional symptoms (&gt;70%), renal involvement (&gt;60%), neurologic diseases (ca. 30%); severe nephritis was more common in MPA. GPA patients had more ENT (82%) and lung diseases (68%). <h3>Conclusions</h3> Japanese patients with CSS, GPA, and MPA respectively showed clinical presentation similar to the patients in western countries, but MPO-ANCA-positive MPA patients were predominating. In addition, the majority of GPA patients showed MPO-ANCA-positive. Surrogate markers for pulmonary vasculits may be useful for MPA classification in Japanese AAV patients. <h3>References</h3> Fujimoto S, et al. Comparison of the epidemiology of ant-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the UK. Rheumatology (Oxford) 50;707-8, 2011. <h3>Disclosure of Interest</h3> None Declared
Feedback and Rewards Part III
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2013)

Formal and informal feedback is important to improve the performance, skill sets, commitment, accountability, and morale of the person being evaluated. Feedback can help people achieve their goals. Feedback is a basis for changes in compensation and other rewards. Formal reviews can also be the foundation for job changes. The latter includes promotions, lateral moves that are a better fit or will help the individual have new experiences or achieve new areas of proficiency, or finding opportunities to work outside the organization.
Maternal Thyroid Deficiency during Pregnancy and Subsequent Neuropsychological Development of the Child
Authors: James E. Haddow, Glenn E. Palomaki, Walter C. Allan, Josephine R. Williams, George J. Knight, June Gagnon, Cheryl E. O'Heir, Marvin L. Mitchell, Rosalie J. Hermos, Susan E. Waisbren, James D. Faix, Robert Z. Klein
Journal: New England Journal of Medicine (1999)

When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known.
Abstract 1496: Proteolytic regulation of the Wnt/PCP pathway in cancer
Authors: Vladislav Golubkov, Natalie Prigozhina, Piotr Cieplak, Alexander Aleshin, Alexey Chekanov, Andrei Chernov, Danhua Zhang, Wenhong Zhu, Khatereh Motamedchaboki, P. Duc Dong, Alex Strongin
Journal: Cancer Research (2011)

Abstract The non-canonical Wnt signaling pathway regulates planar cell polarity (PCP) and directed cell motility in processes as diverse as embryogenesis and cancer cell invasion. Here, we establish that the protein tyrosine kinase-7 (PTK7), an essential component of the Wnt/PCP pathway, strongly inhibits cancer cell invasion by reorganizing the actin cytoskeleton and altering actomyosin contraction. We also demonstrate that the pro-invasive membrane type-1 matrix metalloproteinase (MT1-MMP) functions as a principal sheddase of PTK7 and reverses its inhibition of cell invasion. MT1-MMP directly cleaves the PKP621↓LI sequence localized in an exposed region of the seventh Ig-like domain, generating an N-terminal, soluble PTK7 species (sPTK7) that interacts with membrane PTK7 in a dominant-negative fashion. Protease activity was reciprocally correlated with levels of PTK7 in several cell types and during zebrafish embryogenesis. Reduced PTK7 levels were observed in breast tumours compared to normal breast tissue. Conceptually, our data suggest that the Wnt/PCP pathway converges with pericellular proteolysis to regulate cell motility in normal development and cancer. Further insight into MT1-MMP regulation of Wnt/PCP may promote understanding of directional cell motility in embryogenesis and cancer and lead to identification of therapeutics to treat PCP-related developmental disorders and malignancy. 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 1496. doi:10.1158/1538-7445.AM2011-1496
Abstract 5162: COX-2 downregulation protects SUM-149 cells following targeting of choline phospholipid metabolism
Authors: Noriko Mori, Ioannis Stasinopoulos, Flonne Wildes, Zaver M. Bhujwalla
Journal: Cancer Research (2012)

Abstract Enzymes in the choline phospholipid metabolism pathway such as choline kinase (Chk) and phopholipase D1 (PLD1) are being evaluated as novel targets in cancer therapy since these enzymes are overexpressed in aggressive cancers including breast cancer. We have previously shown that single and double downregulation of Chk and PLD1 significantly reduced cell proliferation in breast cancer cells. We also observed a close association between Chk and cyclooxygenase 2 (COX-2), an inducible enzyme that mediates the inflammatory response and plays a role in cancer invasion, angiogenesis and metastasis. COX-2 inhibition is also being considered as a strategy for cancer prevention or treatment. Here we investigated the effect of the COX-2 downregulation combined with PLD1 and Chk downregulation using siRNA, on cell proliferation to achieve improved control and minimize compensatory responses that allow the cell to survive or adapt. The triple negative inflammatory breast cancer cell line, SUM149, was used in this study. Cells were transfected with 25 nM siRNA against COX-2 (siRNA-cox2), PLD1 (siRNA-pld1) or Chk (siRNA-chk) either singly or combined for 48 h. Untreated cells and the transfection reagent (DharmaFECT) treatment were used as negative controls. Immunoblot analysis was done after 48 h transfection using antibodies specific to COX-2, PLD1, Chk-α, and GAPDH (as a loading control). Proliferation/viability of cells was determined using the CCK-8 assay (cell counting kit-8, Dojindo) at day 2 and day 5 after transfection. After 48 h transfection with siRNA-pld1 or siRNA-chk, PLD1 or Chk-α protein were downregulated significantly and COX-2 protein was upregulated. When we combined downregulation of Chk or PLD1 with COX-2 dowregulation, we established significantly lower COX-2 protein levels compared to single knockdown of Chk and PLD1. COX-2 downregulation alone did not significantly reduce proliferation. Downregulation of PLD1 or Chk, however, significantly reduced proliferation compared to untreated cells (PLD1: –75%, Chk: –68%). When we combined COX-2 downregulation with PLD1 or Chk downregulation, cell survival was significantly higher than with just PLD1 or Chk alone (PLD1: –46%. Chk: –28%). These results suggest that COX-2 downregulation rescues cells following downregulation of PLD1 or Chk in SUM149 cells, identifying a different facet of COX-2 in the choline phospholipid pathway. This work supported by R01 CA82337 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 5162. doi:1538-7445.AM2012-5162
Inhibitory effect of miR-29a on the chondrogenic differentiation of mesenchymal stem cells
Authors: David Guérit, Didier Philipot, Paul Chuchana, Jean-Marc Brondello, Christian Jorgensen, Danièle Noël
Journal: Annals of the Rheumatic Diseases (2012)

We previously reported that a-disintegrin and metalloproteinase (ADAM)17 is a key protease regulating myelin formation. We now describe a role for ADAM17 during the Wallerian degeneration (WD) process. Unexpectedly, we observed that glial ADAM17, by regulating p75<sup>NTR</sup> processing, cell autonomously promotes remyelination, while neuronal ADAM17 is dispensable. Accordingly, p75<sup>NTR</sup> abnormally accumulates specifically when ADAM17 is maximally expressed leading to a downregulation of tissue plasminogen activator (tPA) expression, excessive fibrin accumulation over time, and delayed remyelination. Mutant mice also present impaired macrophage recruitment and defective nerve conduction velocity (NCV). Thus, ADAM17 expressed in Schwann cells, controls the whole WD process, and its absence hampers effective nerve repair. Collectively, we describe a previously uncharacterized role for glial ADAM17 during nerve regeneration. Based on the results of our study, we posit that, unlike development, glial ADAM17 promotes remyelination through the regulation of p75<sup>NTR</sup>-mediated fibrinolysis. <b>SIGNIFICANCE STATEMENT</b> The α-secretase a-disintegrin and metalloproteinase (ADAM)17, although relevant for developmental PNS myelination, has never been investigated in Wallerian degeneration (WD). We now unravel a new mechanism of action for this protease and show that ADAM17 cleaves p75<sup>NTR</sup>, regulates fibrin clearance, and eventually fine-tunes remyelination. The results presented in this study provide important insights into the complex regulation of remyelination following nerve injury, identifying in ADAM17 and p75<sup>NTR</sup> a new signaling axis implicated in these events. Modulation of this pathway could have important implications in promoting nerve remyelination, an often-inefficient process, with the aim of restoring a functional axo-glial unit.
Case 22-2002
Authors: James T. Noble, Eugene J. Mark
Journal: New England Journal of Medicine (2002)

Presentation of CaseA 37-year-old man was admitted to the hospital because of three weeks of intermittent fever and abdominal and back pain.The patient had been well until about seven months earlier, one month after he had begun a difficult trip by land from his native Peru to the United States. During his trip, which took four months, he ate fruit directly from trees, bathed in and drank water from rivers and other uncertain sources, passed through several tropical rain forests, and received numerous mosquito bites. In Guatemala, about 7 months before admission, he had a fever that lasted . . .