tbuckley/cabot-search huggingface dataset:
Abstract 423: Decipher the molecular mechanisms by which syndecan-1 in breast cancer stroma fibroblasts regulates extracellular matrix fiber organization and carcinoma cell motility
Authors: Ning Yang, Andreas Friedl
Journal: Cancer Research (2011)

Abstract The cell surface proteoglycan syndecan-1 (Sdc1) is frequently induced in the stromal fibroblasts of invasive breast carcinomas. We have recently identified a striking correlation between stromal Sdc1 expression and extracellular matrix (ECM) fiber architecture, both In vivo (in human breast carcinoma samples) and in vitro. Bioactive, cell-free 3D ECMs generated from cultures of Sdc1-positive human mammary fibroblasts (HMF), termed ECM-Sdc1, showed an organized, aligned fiber architecture, which contrasted markedly with the random fiber arrangement seen in the ECM of Sdc1-negative HMFs (ECM-mock). We further demonstrated that aligned ECM fiber architecture was responsible for the enhanced directional migration and invasion of the breast carcinoma cells when seeded into the fibroblast-free ECM-Sdc1. To decipher the molecular mechanisms responsible for the formation of an invasion-permissive ECM, a series of Sdc1 mutants was introduced into HMF. These include a heparan sulfate (HS) -deficient, a cytoplasmic domain (CD) deletion and a transmembrane domain (TMD) substitution mutant. Early experiments suggest that HS are required for the activity of Sdc1 in regulating ECM alignment, while TDM is dispensable. Integrins play a key role in the assembly of the provisional fibronectin-rich ECM and Sdc1 has been shown to be an important regulator of integrin activity. Therefore, we have begun to investigate the the role of integrins in Sdc1-mediated ECM fiber alignment. HMF expresses various integrins, as determined by Western blotting and flow cytometry. Using siRNA oligos, we are targeting different integrin subunits including α4, α5, αV and β3 to determine, which integrins are responsible for Sdc1-dependent ECM fiber alignment and consequently the invasion-permissive properties of the ECM. A better understanding of the mechanisms governing ECM organization may lead to the development of novel stroma-targeted therapy for breast cancer. 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 423. doi:10.1158/1538-7445.AM2011-423
A8.22 The role of proinflammatory and anti-inflammatory cytokines on CD3ζ-chain expression of human T- lymphocytes
Authors: Nikolett Marton, Barbara Molnár-Érsek, Edit Buzás, György Nagy
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> ζ-chain has an important role in T-lymphocyte activation, and decreased ζ-chain expression is common at the sites of chronic inflammation. The precise mechanism of the ζ-chain downregulation is not known. Our earlier data suggested that CD3 ζ-chain expression of T-lymphocytes isolated from patients with rheumatoid arthritis, was lower than that of the healthy donors (p &lt;0.05), and tumor necrosis factor (TNF) modulated T cell activation during inflammation by regulating the amount of CD3ζ-chain expression via a Src-like adaptor protein (SLAP) dependent mechanism. Our objective was to study the effect of proinflammatory and anti-inflammatory cytokines on the ζ-chain expression. <h3>Materials and Methods</h3> PBMCs were separated from whole-blood samples by density gradient centrifugation. Jurkat cells and PBMCs were cultured in RPMI supplemented with 10% fetal bovine serum. PBMCs were activated with anti-CD3 and anti-CD28 antibodies. Cells were treated with 20 and 80 ng/ml TNF, IL- 1, IL-2, IL-4, IL-6, IL-8, IL-10; IL-13, IL-17 and IL-35 for 24 hours or left untreated. ζ-chain expression was measured by Western blot and by flow cytometry. <h3>Results</h3> IL-6, IL-8, IL-10, IL-13 and IL-17 downregulated CD3ζ-chain expression (p&lt;0.05), similarly to TNF. <h3>Conclusion</h3> Our present data indicate that both proinflammatory and anti-inflammatory cytokines may have a role on T-cell activation through regulating CD3ζ-chain expression.
AB0349 Effectiveness of insole use on rheumatoid feet: a randomized controlled trial
Authors: E. Moreira, A. Jones, H. V. Oliveira, F. Jennings, A. Fernandes, J. Natour
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by peripheral polyarthritis, which may cause joint destruction and deformities, resulting in reduced function and disability. RA patients ofter have foot joint involvement in 85-100% of the cases. The use of insoles has been a routine in the treatment of rheumatoid feet, despite the weak evidence. <h3>Objectives</h3> To assess the effectiveness of the use of insoles for foot pain, function, gait analysys, foot load distribution, quality of life and patient satisfaction regarding the use of the insoles in patients with RA. <h3>Methods</h3> Eligible patients included women classified as RA according to the ACR criteria, aged 18-65 years old with pain in feet between 3 and 8 on a 10-cm pain scale (END) for walking; functional classes I, II, and III. Of the 208 patients evaluated, 80 met the eligibility criteria and were randomized into experimental (EG) or control groups (CG). The EG group made use of EVA insoles with arch support and medial retrocapital support, and CG group employed flat insoles during the study. Pacients were evaluated for pain (VAS) when walking and at rest, function (HAQ), function of the feet (FFI), quality of life (SF-36), 6-minute walk test, Likert scale, and examination of baropodometry dynamics (Pro FootWalk, AMcube ®, Gargas, France) at baseline, 45 days (T45), 90 days (T90) and 180 days after the onset of the use of the insoles by a blinded evaluator. <h3>Results</h3> Thirty-nine and 41 patients were randomly divided into EG and CG groups, respectively. In the comparison between the groups using ANOVA for repeated measures, we found better results for the EG with a statistical difference for the variables END walking and at rest on the right and left foot with p &lt;0.001 for all these variables, stride length (p = 0.001), and Likert scale (p = 0.039). For other variables, we found no statistically significant difference between groups. <h3>Conclusions</h3> The use of insoles with medial arch and retrocapital support is effective in reducing pain when walking and at rest on both feet, increasing stride length and satisfaction with the use of insoles. <h3>References</h3> Chalmers AC, Busby C, Goyert J, Porter B, Schulzer M. Metatarsalgia and rheumatoid arthritis: a randomized, single blind, sequential trial comparing 2 types of foot orthoses and supportive shoes. J Rheumatol. 200;27(7):1643-47. Farrow SJ, Kingsley GH, Scott DL. Interventions for foot disease in rheumatoid arthritis: a systematic review. Arthritis Rheum 2005;53:593-602. <h3>Acknowledgements</h3> FAPESP and CAPES <h3>Disclosure of Interest</h3> None Declared
RNA interference–induced hepatotoxicity results from loss of the first synthesized isoform of microRNA-122 in mice
Authors: Paul N Valdmanis, Shuo Gu, Kirk Chu, Lan Jin, Feijie Zhang, Elizabeth M Munding, Yue Zhang, Yong Huang, Huban Kutay, Kalpana Ghoshal, Leszek Lisowski, Mark A Kay
Journal: Nature Medicine (2016)
Abstract 4057: Mono-ubiquitination of Smad2/3 by Smurf2 regulates TGF-β transcriptional response
Authors: Liu-Ya Tang, Motozo Yamashita, Yi Tang, Ying E. Zhang
Journal: Cancer Research (2011)

Abstract Transforming growth factor-beta (TGF-β) regulates a wide array of biological processes ranging from proliferation to apoptosis, and alterations in its signalling pathway are associated with a variety of human diseases, including cancer. Through Smad proteins, TGF-β signal can be propagated into nuclear transcription machinery. Thus, fine tuning of Smads activity is crucial for TGF-β signal transdction. Smad ubiquitination regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase and previous data shows that Smurf2 negatively regulates TGF-β signaling by inducing polyubiqutination and degradation of Smad proteins. Here, we find a different type of ubiquitination – mono-ubiquitination of Smad2/3 by Smurf2. Smad2/3-Smurf2 interaction and Smad2/3's mono-ubiquitination by Smurf2 are enhanced by TGF-β induced linker phosphorylation. The ubiquitination depends on Smad2/3's PY motif and Smurf2's E3 ligase activity. Cycloheximide treatment assay revealed that this ubiquitination has no effect on Smad2/3 protein stability, but the transcriptional activity is inhibited as shown by both luciferase assay and real-time PCR analysis. Thus, our findings reveal a novel regulatory role of Smurf2 in TGF-β signaling. 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 4057. doi:10.1158/1538-7445.AM2011-4057
Prognostic Importance of Cytogenetic Abnormalities in Patients with Chronic Lymphocytic Leukemia
Authors: Tin Han, H. Ozer, N. Sadamori, L. Emrich, G. A. Gomez, E. S. Henderson, M. L. Bloom, A. A. Sandberg
Journal: New England Journal of Medicine (1984)

Chronic lymphocytic leukemia is recognized as having a variable prognosis, but its staging has depended exclusively on anatomical sites of involvement and the presence or absence of anemia and thrombocytopenia. The recent availability of techniques permitting cytogenetic analysis of malignant B lymphocytes led us to examine the karyotypic abnormalities in chronic lymphocytic leukemia and to correlate them with clinical stage, progression of disease, and survival. Of 53 patients with metaphases adequate for study who were followed for a minimum of one year, 21 (40 per cent) had abnormal karyotypes, of which trisomy 12 was the most frequent (25 per cent). Abnormal karyotypes were found to be significant correlates of advanced clinical stage (P less than 0.005) and of shortened survival (P less than 0.05). We conclude that cytogenetic analysis provides useful clinical and prognostic information in patients with chronic lymphocytic leukemia.
Abstract P1-13-06: Health Resource Utilization Associated with Skeletal-Related Events in Patients with Bone Metastases: Interim Analysis Results from the US Breast Cancer Cohort of a Multinational Observational Study
Authors: A Mahmood, R Robles, H Ghazal, C Atchison, R Wei, K Chung, J. Pinzone
Journal: Cancer Research (2010)

Abstract Background: Bone metastases are common in women with advanced breast cancer and are frequently associated with skeletal-related events (SREs). The burden of individual SRE types on health resource utilization (HRU) indicators in breast cancer has been only minimally described. Methods: The aim of this ongoing observational, prospective, multinational study is to assess, by tumor type, the amount of HRU associated with different SRE types including pathologic fracture, surgery or radiation to bone, and spinal cord compression. Patients with breast, prostate, or lung cancer and bone metastases or multiple myeloma were enrolled after experiencing a SRE. Inpatient hospitalizations, length of stay, outpatient visits, emergency room visits, nursing home/long-term care facility stays, home health visits, procedures, and medications were collected for the period 90 days prior to enrollment and prospectively to a maximum of 18 months. Each patient could contribute multiple SREs. The investigator determined which HRU were attributed to each SRE. This abstract describes interim analysis data from the US breast cancer cohort; final analysis data will be available 9/2010. Results: As of 12/1/2009, 67 patients contributed 119 SREs for the HRU analyses across 25 US sites. Patient mean [SD] age was 61 [12] years, all patients were female, and 27% discontinued the study (most due to death). Mean duration of follow-up was 9.9 months. HRU for each of the SRE types are shown in the table. Table. Mean and median number of HRU per SRE during the study period by SRE type in patients with breast cancer Conclusion: In this interim analysis of advanced breast cancer patients in the US, SREs are associated with considerable HRU, with the nature and extent of HRU varying depending on the SRE type. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-06.
P0234 : A TGF-beta genomic signature in intrahepatic cholangiocarcinoma highlights a novel long non coding RNA located in the nuclear paraspeckles of tumor cholangiocytes
Authors: A. Merdrignac, G. Angenard, D. Bergeat, A. Fautrel, B. Turlin, K. Boudjema, B. Clément, L. Sulpice, C. Coulouarn
Journal: Journal of Hepatology (2015)
S24 Differentiated primary bronchial epithelial cell (pBECs), monocyte derived macrophages (MdMs) and monocyte derived dendritic cells (MODCs) transwell co-culture: Respiratory Syncytial Virus (RSV) infection of the apical and basolateral surfaces
Authors: K. B. Ugonna, K. Plant, M. L. Everard
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> RSV causes winter epidemics of respiratory disease. Active infection is virtually absent in summer months. Infected ciliated airway epithelial cells, local macrophages and dendritic cells secrete cytokines including interleukins (IL) 6 and 8, promoting a strong neutrophilic response that is important in disease clearance and airway inflammation. <i>In vitro</i>, RSV is capable of infecting MoDCs. RSV inhibits their maturation and can remain dormant in these cells. Dormant RSV can be stimulated to replicate with exogenous nitric oxide. These MoDCs are then able to re-infect HeLa cells (a lab strain of immortalised cervical cells). The following hypothesis was explored: <i>Infected dendritic cells act as a reservoir for RSV over summer months</i>. <h3>Aim</h3> The aim of this study was to investigate the effect of RSV on pBEC and MoDc cell lines across a semi permeable membrane in the presence of MdMs. <h3>Methods</h3> Primary bronchial epithelial cells were seeded in the apical part of the transwell model at 1×10<sup>6</sup> cells per ml and differentiated over 21 days on an air liquid interface. MoDCs were seeded on the basolateral part of the transwells at 1×10<sup>6</sup> cells/ml. MdM were seeded on top of the epithelial layer in selected experiments (see Abstract S24 Figure 1). Red fluorescent RSV (rr-RSV) was added to the apical side at a concentration of 1×10<sup>6</sup> plaque forming units (pfu)/ml with un-infected MoDCs on the basolateral side, and uninfected pBECs in the apical side were co-cultured with MoDCs previously infected with rr-RSV at 5 × 10<sup>5</sup> pfu/ml. Controls were uninfected pBECs with uninfected MoDCs or with just media on basolateral side. Red fluorescence (marker for active infection) was measured at 24, 48 and 168 h by flow cytometry. <h3>Results</h3> Directly exposed pBECs and MoDCs were infected at 24 h. Indirectly exposed pBECs were infected at 48 h. Indirectly exposed MoDCs were infected only when MdMs were present on the overlying epithelial cell layer. <h3>Conclusions</h3> RSV is able to infect MoDCs and pBEC across a semi-permeable membrane in our <i>in vitro</i> model of airway epithelium, supporting MoDCs as a potential summer reservoir of RSV.
TCTAP C-041 Unexpected Events on Floating Unapposed Drug Eluting Stent Strut (Dark Side of Stent Strut)
Authors: Hyuck Jun Yoon, Seung-Ho Hur, Chang-Wook Nam, Yun-Kyeong Cho, Jong Yop Pae, Kwon-Bae Kim
Journal: Journal of the American College of Cardiology (2015)
Abstract LB-17: NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma
Authors: Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi
Journal: Cancer Research (2012)

Abstract Emerging evidence, though currently sparse, suggests that “lineage-specific transcription factors” with developmental roles in normal progenitor cells of particular lineages may also confer dependency for survival to certain types of cancer cells. Accumulated evidence indicates that NKX2-1, a lineage-specific transcription factor also known as TITF1 and TTF-1, which is expressed in a major fraction of lung adenocarcinomas, plays essential roles in peripheral lung development. We previously identified NKX2-1 as a lineage-survival oncogene in lung adenocarcinoma, while other investigators reached similar conclusions through genome-wide searches for focal genomic aberrations. Previous findings including ours thus clearly indicate the requirement of sustained NKX2-1 expression for lung adenocarcinoma survival, while it remains elusive how NKX2-1 mediates survival signals. In the present study, we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and proapoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation. Interestingly, ROR1 was also identified as a receptor tyrosine kinase with a “sustainer role” for the interaction of EGFR-ERBB3 and ERBB3 phosphorylation in a ROR1 kinase-independent manner, consequentially leading to PI3K activation. It was also of note that ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Secondary EGFR mutation, MET amplification, and HGF overexpression may arise in lung adenocarcinomas in patients undergoing EGFR-TKI treatment, leading to treatment resistance. The existence of such diverse mechanisms makes it difficult to predict which should be targeted to prevent expansion of resistant clones. From a clinical point of view, it is thus of particular interest that ROR1 inhibition appears to be effective for treatment of gefitinib-resistant lung adenocarcinomas with various resistance mechanisms. Taken together, the present findings identify ROR1 as an “Achilles’ heel” in lung adenocarcinomas. Future development of novel therapeutic means including ROR1-specific antibodies and small molecules that inhibit both or either of the two distinct prosurvival signal-sustaining functions is greatly anticipated for attempts to reduce the intolerable death toll from currently “hard-to-cure” lung adenocarcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-17. doi:1538-7445.AM2012-LB-17
THU0009 Differential expression of DKK1 in synovial fibroblasts from resolving and early rheumatoid arthritis
Authors: M. Juarez, D. Scheel Toellner, L. Yeo, K. Howlett, R. Bayley, B. de Paz, R. Hardy, K. Raza, M. Cooper, C. Buckley, A. Filer
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Mechanisms preventing the resolution of inflammation and promoting joint damage underlie the persistence of RA and the development of damage early in disease. Dickkopf related protein 1 (DKK1) is an inhibitor of the Wnt signalling pathway involved in osteoblast growth and differentiation and cell adhesion and invasion in health and disease. In cancer, increased plasma levels of DKK1 are associated with osteolytic lesions in multiple myeloma and with solid tumour invasion and progression. In rheumatoid arthritis (RA), increased DKK1 plasma levels correlate with inflammation and the presence of bone erosions <h3>Objectives</h3> We aimed to identify differences in expression of key stromal genes including DKK1 in synovial fibroblasts from patients from three different clinical outcome groups: very early RA, established RA and spontaneously resolving arthritis <h3>Methods</h3> Synovial tissue biopsies were obtained from 12 early synovitis patients who developed RA (according to 1987 ACR criteria within 18 month follow-up) and 8 early synovitis patients with self-limiting disease. All samples were collected within 12 weeks of the onset of any musculoskeletal symptom attributed to inflammatory arthritis. In addition, 9 patients with established RA (according to 1987 ACR criteria with a symptom duration of &gt;3 months at sample collection), were studied. Synovial fibroblasts were cultured and expanded to passage 3 using established methods. mRNA expression for a range of stromal genes was quantified using real-time quantitative PCR. Values were expressed as 2<sup>-dCt</sup> relative to GAPDH. DKK1 levels were measured in the supernatants of cultured cells using a commercial ELISA kit (R&amp;D sytems) <h3>Results</h3> Amongst differentially expressed genes, DKK1 expression was significantly higher in synovial fibroblasts from patients with early RA than in those from patients with resolving arthritis (0.024 vs. 0.009, p&lt;0.005). Differential expression was also observed at the protein level (23.2 ng/ml (11.1-48.5) vs. 6.6 ng/ml (4.2-23.6), p=0.07). There was no differential expression of DKK1 in early RA and established RA groups. Expression levels of DKK1 mRNA or protein did not correlate with disease duration, or with clinical indices <h3>Conclusions</h3> DKK1 is an inhibitor of the Wnt signalling pathway that has been shown to promote cell invasion and a pro-destruction imbalance of osteoblast and osteoclast activity. Our data suggest that expression of DKK1 by fibroblasts cultured from treatment naive patients discriminates between persistent and resolving disease, and occurs early in the disease process in RA <h3>Disclosure of Interest</h3> None Declared