tbuckley/cabot-search huggingface dataset:
ET-59 * DEVELOPMENT AND CHARACTERIZATION OF A MEK1 INHIBITOR (AZD6244) SENSITIVE CHILDHOOD ASTROCYTOMA CELL LINE
Authors: A. Studebaker, H. Bid, D. Phelps, P. Houghton
Journal: Neuro-Oncology (2014)

We previously characterized the development and reversal of acquired resistance to the MEK1 inhibitor AZD6244 in an in vivo model of childhood astrocytoma. The BT-40 astrocytoma xenograft model expresses mutated BRAFV600E and is highly sensitive to AZD6244, but acquires resistance, which can be overcome with the addition of the STAT3 inhibitor LLL12. The purpose of this current study was to establish and characterize a cell line derived from the xenograft model as well as develop an orthotopic mouse model. Sensitivity to AZD6244 and LLL12, expression-profiling assessment of MEK signature and compensatory pathways, and cytokine levels were assessed in the newly developed BT-40 cell line. The BT-40 cell line exhibited sensitivity to AZD6244 and LLL12 with IC50 values of 350nM and 1 µM, respectively. Combination treatment was additive. Treatment with AZD6244 inhibited p-Erk and the mTOR downstream signaling molecule p-S6, while p-Akt, p-STAT3, p-4E-BP1 increased. Kinase expression arrays performed on cells treated with AZD6244 showed a decrease in IL-1α, G-CSF, and IL-6 and an increase in CXCL10. The decrease in IL-6 was restored to baseline levels with the addition of LLL12. Interestingly, the JAK2 inhibitor AZD1480 failed to restore the IL-6 levels. The IL-6 results observed in the expression arrays were confirmed by ELISA. The BT-40 cell line, along with a cell line stably expressing luciferase (BT-40Luc), were implanted into the caudate putamen using stereotaxic guidance. The BT-40Luc cells exhibited exponential growth over time as evaluated with bioluminescent imaging. In conclusion, a cell line derived from a previously described in vivo model of childhood astrocytoma was developed that closely recapitulated our original findings in the xenograft model following treatment with the MEK1 inhibitor AZD6244. Furthermore, an orthotopic model of these cells was developed, which will allow us to characterize response to established and novel therapeutic agents. Supported by PHS award CA169368.
Genes Regulating the Progression of Human Ductal Carcinoma In Situ to Invasive Breast Cancer.
Authors: S. Lee, Y. Wu, B. Dao, A. Lim, D. Medina, S. Stewart, D. Allred
Journal: Cancer Research (2009)

Abstract Rationale: The progression of human ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) represents a major potentially life-threatening event. Our understanding of this process is rudimentary. Improved understanding could lead to better ability to predict and new therapeutic strategies to prevent progression, which would be major contributions to health care. Objectives: To identify genes involved in regulating the progression of human DCIS to IBC, and to confirm their involvement utilizing relevant in vitro and in vivo model systems. Methods: Gene expression profiles were evaluated in five complimentary cohorts of human DCIS and IBC (total n=59 in each category) using cDNA microarray technology. Supervised statistical comparisons were used to identify differentially expressed genes in each cohort. The genes were distilled to top priority candidates by the following vetting strategy: (1) expression changed in same direction in 2 or more cohorts; and (2) they possessed known biological functions which might reasonably be involved in regulating tumor invasion; and (3) they had not been studied in the context of breast cancer invasion. Initial studies have focused on candidate invasion-suppressor genes (down-regulated in IBC vs. DCIS). A human DCIS-like cell line (DCIS.COM) was stably transduced with shRNAi against the genes (3-5 hairpins each) and evaluated in vitro and in vivo for changes in invasion-related behaviors vs. controls (growth and migration in 2D and 3D cell cultures, invasion in 3D culture, and a human-in-mouse [HIM} DCIS xenograft model). The latter is a novel method we developed where cells are injected into the nipple duct of intact mammary glands of immune-compromised mice. They initially grow as DCIS which progress to IBC at varying rates depending on the cells. Results: Two novel invasion-suppressor genes (CSTA and FAT1) were identified based on demonstrating significantly increased growth, migration, and invasion in the assays described. In particular, shCSTA (n=22) and shFAT1 (n=22) HIM DCIS xenografts progressed to large IBCs by 10 weeks or less, significantly (P&amp;lt;.0001) greater than observed in controls (n=26) (67%, 64%, vs. 26%, respectively). Conclusions: We have identified two genes (CSTA and FAT1) whose normal functions appear to suppress the progression of human DCIS to IBC. These results could lead to new therapeutic strategies to prevent or suppress progression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6141.
Abstract 4214: Identifying cell surface receptor VAP targets to sensitize melanoma to chemotherapy
Authors: Xiaowen Sun, Kris A. DeMali
Journal: Cancer Research (2012)

Abstract Melanoma accounts for 79% of all skin cancer deaths. The incidence rate has doubled throughout the past three decades, while the survival rate remains consistently low. Melanoma is unusually lethal as it metastasizes early and is highly resistance to all available chemotherapeutics. The newest treatment utilizes a small inhibitor targeting the BRAF pathway, considering the BRAF V600E mutation occurs in 65% of clinical melanoma cases. Unfortunately, it is clear that there is both primary and acquired resistance to the drug. Recent studies demonstrate that engaging defective cell surface adhesion receptors known as integrins increases the sensitivity of melanoma to traditional DNA damaging agents. Our laboratory has identified a novel peptide denoted vinculin activating peptide (VAP) that increases integrin engagement from within the cell by targeting the integrin cytoplasmic binding partner, vinculin. Furthermore, VAP sensitizes melanoma to DNA damaging agents in vitro and in vivo. The goal of this project is to identify the cell surface target of VAP. Both α1and β3 integrins are highly over-expressed in melanoma, suggesting that VAP targets one or both of these defective integrins. To test this possibility, melanoma cells lacking β1 or β3 integrins were generated. In the absence of β1 integrins, VAP did not induce elevations in p53 levels or increase apoptosis in melanoma cell lines treated with cytotoxic agents. In addition, its ability to sensitize melanoma cells to therapeutics in biological assays was ablated. Furthermore, the β1 integrin-dependency of VAP's effect was confirmed by examining melanoma cells lacking β3 integrins. Ongoing experiments are testing the requirement for β1 integrin in mouse models of melanoma. Taken together, these findings suggest that β1 integrins are required for VAP to sensitize melanomas to chemotherapy agents. The successful completion of these studies will provide the mechanistic underpinning for a new class of therapeutics that sensitize melanomas to chemotherapy. 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 4214. doi:1538-7445.AM2012-4214
THU0039 Evidence of HLA-B27 in healthy individuals and patients with uveitis is a risk factor for alterations in bone metabolism
Authors: S. Schmidt, S. Finzel, J. Rech, M. Englbrecht, R. Said-Nahal, M. Breban, G. Schett
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> HLA-B27 is strongly associated with the development of spondyloarthritis (SPA), a disease characterized by new bone formation and ankylosis of joints and intervertebral spaces. We have recently shown the role of the two Wnt antagonists, dickkopf 1 (Dkk1) and sclerostin in new bone formation in SPA. We therefore hypothesized that HLA-B27 itself may be associated with alterations in expression of Dkk1 and sclerostin. <h3>Objectives</h3> To test whether positivity for HLA-B27 <i>per se</i> is associated with changes of biomarkers of the Wnt pathway. <h3>Methods</h3> Sera of 31 patients with HLA-B27 positive SPA, 30 patients with HLA-B27 positive uveitis, 30 healthy carriers of HLA-B27 as well as 90 age and gender matched HLA-B27 negative healthy controls were examined for total Dkk1 and sclerostin levels by enzyme-linked immunosorbent assays (ELISA). Statistical analysis was done by one-way analysis of variance (ANOVA). <h3>Results</h3> Healthy HLA-B27 positive individuals showed significant lower levels of Dkk-1 compared with the negative controls (p=0.01). Moreover, Dkk1 levels were reduced in all three HLA-B27 positive groups, even in healthy HLA-B27 carriers. Additionally, serum levels of sclerostin were higher in HLA-B27 negative controls than in SPA HLA-B27 carriers. <h3>Conclusions</h3> HLA-B27 positivity is associated with low levels of Dkk1 and sclerostin independent from the presence of clinical symptoms of SPA. Both HLA-B27 healthy carriers as well as HLA-B27 associated uveitis without SPA show lower levels of these two Wnt antagonists than normal HLA-B27 negative controls. These data suggest that alterations in bone metabolism even occur in the absence of clinical SPA and are associated with HLA-B27 carriage. <h3>Disclosure of Interest</h3> None Declared
“False-Negative” Meckel’s Scan Caused by a Recent Barium Study
Authors: NIR HOD, LILIA MINDLIN, TIFHA HORNE
Journal: Clinical Nuclear Medicine (2002)

From the Department of Nuclear Medicine, Assaf Harofeh Medical Center, Zerifin, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Received for publication March 19, 2001. Revision accepted June 20, 2001. Reprint requests: Dr. Tifha Horne, Department of Nuclear Medicine, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
AB0460 Long-term remission with golimumab in active rheumatoid arthritis patients despite methotrexate through 2 years
Authors: E. Keystone, M. Genovese, L. Klareskog, S. Xu, C. Han, E. Hsia
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To assess long-term remission through 2 yrs from GO-FORWARD. <h3>Methods</h3> Retrospective analysis of GO-FORWARD (RA pts with inadequate response to MTX) thru Wk104. Active RA (N=444) pts despite MTX were random'd to PBO+MTX, GLM100mg+PBO, GLM50mg+MTX, or GLM100mg+MTX, Pts with &lt;20% improvmnt in SJC/TJC at wk16 entered EE: PBO+MTX$→ $GLM50mg+MTX, GLM 100mg+PBO$→ $GLM100mg+MTX, GLM 50mg+MTX$→ $GLM100mg+MTX. At Wk24, pts on PBO+MTX, crossed over to GLM 50mg+MTX. GLM/PBO was inj q4wks. Remission rates at Wk24, and the propor who remained in remission at Wks52&amp;104 were assessed using 4 def'n: DAS28 (weighted sum of SJC/TJC, 28 joints, CRP, and ptGA); EULAR Boolean(DefA) TJC/SJC, 28 joints, CRP mg/dL, and ptGA, each score ≤1; EULAR SDAI (Def B)-SDAI score is sum of TJC/SJC, 28 joints, ptGA, phyGA, and CRP mg/dLwith scoring ≤3.3; and CDAI (sum of SJT/TJC, 28 joints, ptGA, phyGA ≤2.8). Among those who didn't achieve remission at Wk24, propor of pts who later achieved remission at Wks52&amp;104 using each def are presented. Observed data was used. <h3>Results</h3> At Wk24, sig greater propor of pts achieved remission in the GLM+MTX grps vs PBO+MTX(Table1). At Wk52, ∼80% of pts in the GLM+MTX grp remained in remission using DAS28, SDAI, and CDAI;∼70% remained in remission using Boolean def. At Wk104, among those GLM+MTX pts who achieved remission at Wk24, the propor of pts with sustained remission were: DAS 28 ∼90%, Boolean def ∼55%, and SDAI and CDAI∼65% each. Approx 20% of pts who didn't achieve remission at Wk24, did achieve remission at Wks52&amp;104, with higher rates using DAS28∼30%, and slightly lower rates using Boolean def∼15%. <h3>Conclusions</h3> Using any of 4 remission criteria, GLM+MTX induced remission in a greater propor of pts than PBO+MTX and remission was sustained in the majority of those pts through yrs1 and 2. <h3>Disclosure of Interest</h3> E. Keystone Consultant for: Janssen Research &amp; Development, Inc, M. Genovese Consultant for: Janssen Research &amp; Development, Inc, L. Klareskog Consultant for: Janssen Research &amp; Development, Inc, S. Xu Employee of: Janssen Research &amp; Development, Inc, C. Han Employee of: Janssen Research &amp; Development, Inc, E. Hsia Employee of: Janssen Research &amp; Development, Inc
Abstract 2100: Preclinical evaluation of PF-04691502 in nasopharyngeal carcinoma.
Authors: Herbert H. Loong, Eric C H Wong, Connie W C Hui, Cecilia P Y Lau, Edwin P. Hui, Brigette B Y Ma, Anthony T C Chan
Journal: Cancer Research (2013)

Abstract Nasopharyngeal carcinoma (NPC) is common in Southeast Asia. PF-04691502 (PF) is a novel potent dual inhibitor of PI3K/mTOR capable of inhibiting downstream effectors Akt, S6 and 4E-BP1, resulting in suppression of protein synthesis and cell survival. Five NPC cell lines include two well differentiated cell lines CNE-1 and HK1, two poorly differentiated NPC cell lines CNE-2 and HONE-1, and an undifferentiated NPC cell line C666-1 were selected for this preclinical study. All cell lines expressed basal level of Akt and p70S6K in both phosphorylated and total forms. The cytotoxicity of PF on NPC was evaluated by MTT assay. Cells were incubated in PF with increasing concentration (0.1nM, 50nM, 100nM, 200nM, 500nM, 1μM and 10μM) in culture medium for either 48 hours or 72 hours. Maximum growth inhibition was achieved in over 80% in 72 hours of PF incubation. The IC50 of all cell lines were in hundred nanomolar range (CNE-1 = 276nM, CNE-2 = 84nM, HK1 = 121nM, HONE-1 = 157nM and C666-1 = 395nM). Two most sensitive cell lines (CNE-2 and HK1) together with the least sensitive one (HONE-1) were selected to further evaluate the effect of PF on cell cycle, apoptosis and Akt signaling. Cells treated with either 100nM or 500nM PF for 6 hours and 24 hours were evaluated by cell cycle analysis and G0/G1 arrest was observed at 24 hour time point. Apoptotic effect was indicated by increasing cleaved PARP expression in which 500nM PF treatment for 24 hours induced apoptosis in CNE-2 and HK1 but not in HONE-1. At 48 hours, a lower dose of PF at 100nM could induce apoptosis in all NPC cell lines. The expression of pi-mTOR, pi-p70S6K, pi-Akt(S473), pi-Akt(T308), pi-S6 and pi-4EBP1 was inhibited in by PF, suggesting its effectiveness in anti-proliferation and inhibition of protein synthesis. Antitumor activity was observed in NPC xenograft model after 2 weeks of 10mg/kg PF administration to tumor bearing female athymic nude mice. Both tumor volume and tumor weight in the treatment group were significantly smaller and lighter than that in vehicle group (3.17cm3 vs. 5.58cm3 at 18 days, p=0.005 and 146mg vs. 284mg, p=0.001 respectively) while the body weight between groups were comparable, suggesting this working dose was well-tolerated. The beneficial effects of PF-09641502 in both in vitro and in vivo studies for NPC warrant a further investigation. Acknowledgement: This work is supported by an independent research grant from Pfizer. *Co-authorship Citation Format: Herbert H. Loong, Eric C H Wong, Connie W C Hui, Cecilia P Y Lau, Edwin P. Hui, Brigette B Y Ma, Anthony T C Chan. Preclinical evaluation of PF-04691502 in nasopharyngeal carcinoma. [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 2100. doi:10.1158/1538-7445.AM2013-2100
Abstract 4600: The role of COUP transcription factors in Tamoxifen resistant breast cancer cells
Authors: Omar Z. Maniya, Alan Zwart, Li Chen, Jianhua Xuan, Robert Clarke, Rebecca B. Riggins
Journal: Cancer Research (2010)

Abstract Breast cancer affects 180,000 women in the United States every year, killing over 40,000 of them. The most common type of breast cancer, which expresses the Estrogen Receptor (ER+), has been clinically treated with the antiestrogen Tamoxifen (TAM) for decades. However, up to 35% of patients taking TAM may develop resistance to the drug. This may be related to the fact that ER+ breast cancers are divided into Invasive Lobular Carcinomas (ILC) and Invasive Ductal Carcinomas (IDC), which may have different mechanisms for TAM resistance. Thus, TAM resistance represents a formidable challenge in the treatment of breast cancer. TAM is an antagonist of estrogen receptor alpha (ERalpha), and prevents estrogen-dependent growth signaling in breast tissues. We have published that overexpression of the orphan nuclear receptor, estrogen related receptor gamma (ERRgamma), leads to TAM resistance in ER+ breast cancer cell lines derived from ILC. We have recently found that ERRgamma is also overexpressed in the IDC-derived RR TAM resistant cell line (but not in other models of TAM resistance). This leads us to hypothesize that other orphan nuclear receptors may have been overlooked in prior studies of TAM resistance, and that different members of the nuclear receptor superfamily play unique roles in ILC- and IDC-derived TAM resistant breast cancer. To test this hypothesis, we profiled mRNA expression of the nuclear receptor superfamily in two pairs of TAM sensitive and resistant cells: the IDC-derived MCF7 and RR, and the ILC-derived MDA-MB-134VI and TAM-R. Expression of two members of the COUP transcription factor family was significantly changed. NR2F1 (COUP-TFI) was highly overexpressed in RR cells, and NR2F2 (COUP-TFII) was highly overexpressed in both RR and TAM-R cells relative to sensitive controls. These findings are highly significant as COUP transcription factors have been implicated in embryonic stem cell pluripotency, and NR2F1 has been previously shown to interact with and enhance ERalpha activity through increasing its phosphorylation by MAPK. Therefore, overexpression of NR2F1 (and possibly NR2F2) may counteract the antagonistic effects of TAM and represent a novel pathway for TAM resistance in lobular and ductal ER+ breast cancers. Ongoing studies include gel electrophoresis to determine whether this overexpression is observed at the protein level and siRNA knockdown experiments to determine the impact of NR2F1 and NR2F2 on ERalpha phosphorylation and activity, TAM resistance, cell death, and overall survival. 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 4600.
PARE0009 Treatment-safety pocket fact-sheets for rheumatoid arthritis patients
Authors: S. Trope Chirol, G. Thibaud
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid arthritis (RA) requires immunosuppressive treatments. Patients who are taking these require a specific surveillance and need to be aware of related safety issues. <h3>Objectives</h3> The objective of our project was to produce easy-to-carry information fact-sheets containing relevant and medically-sound data on various RA treatements. <h3>Methods</h3> ANDAR, a French non profit patient organization, gathered RA patients to design the most convenient/efficient format for such patient information fact-sheets. Then, a scientific committee composed of rheumatologists produced the content with the help of ANDAR and a patient-centered medical information agency (EmPatient). Two taskforces belonging to the Société Française de Rhumatologie contributed to the content : the Inflammatory Rheumatism Club (which is in charge of working on drug fact-sheets for healthcare professionals) and the Patient Education Taskforce. <h3>Results</h3> Selected RA patients chose a paper format which, once folded, fits in a wallet. Thus, the fact-sheets may be carried everywhere and are available at all time to answer safety-related issues. The scientific committee worked under this constraint to list essential information and key points. The goal was to produce a fact-sheet for each molecule prescribed against RA. These fact-sheets form a collection entitled « Things to know… for a better life with your treatment ». The collection was systematically sent to all hospital-based and independant rheumatologists to distribute to their patients. Fact-sheets are also available for free through ANDAR, nurses and local patient education programs. Each fact-sheet features « Key points to memorize », a detailed explanation of the molecule (action mechanisms, dosage, side effects, etc.), some FAQ and a card to be completed with the brand name and the prescribed dose, in French and in English. <h3>Conclusions</h3> Today, 8 fact-sheets have been produced and more than 34,000 copies (total) have been distributed. Patients and healthcare professionals have expressed their wish to see the missing molecules be included in the collection as soon as possible. <h3>Acknowledgements</h3> We would like to thank Dr Laure Gossec, Dr Laurent Grange, Dr S. Jousse Joulain, Dr Thao Pham, Claude Farès, Anne-Laure Roubaud, la SFR, and Stephane Korsia Meffre. <h3>Disclosure of Interest</h3> None Declared
Abstract 3871: Expression of MACC1, a metastasis-related protein, associated with the progression of colorectal cancer
Authors: Hassan Ashktorab, Pia Herrmann, Edward L. Lee, Hadi Razjouan, William Green, Duane T. Smoot, Hassan Brim, Ulrike Stein
Journal: Cancer Research (2011)

Abstract Background: Colorectal cancer (CRC) as the second most common cancer in western world has different prognostic basis in contrast to other cancers. Its pathologic staging is the main prognostic factor. Recently, MACC1 has been proposed as an effective marker for identifying patients at high risk for the development of distant metastases when MACC1 is highly expressed in the not (yet) metastasized primary tumor. Aims and Methods: We aimed to assess the cellular and sub-cellular expression of MACC1 in age matched normal, adenomatous and cancerous colonic tissue samples. Samples were recruited from pathology department of Howard University Hospital. The Tissue Micro Array (TMA) sections were made from all duplicated samples and put in three different TMA slides as normal matched (n=44), adenomatous (n=60) and adenocarcinoma (n=36). Total of 140 samples were stained for MACC1 by Immuno-Histo-Chemistry method. Then, all three TMA were read by two pathologists including one GI pathologist. The expression were reported as staining 0, 1, 2, 3, 4 which refer to none, less than 10%, 10-25%, 25-50%, 50-75%, &amp;gt;75%, respectively. Sub-cellular staining was reported as nuclear, cytoplasmic, or both. Results: Of 140 samples, 36 were adenocarcinomas (mean age: 64.3; M/F: 16/20); 60 adenomatous (mean age: 64.8; M/F: 31/29); 44 normal controls (mean age 65.8; M/F: 22/22). Adenocarcinomas received score 4 in 86.1% of cases which was significantly higher (p&amp;lt;0.05) than normal (15.9%) and adenomatous (28.3%) cases. MACC1 stained more in cytoplasm (88.6%) in contrast to normal (44.7%) and adenomatous cases (32.1%) with P &amp;lt; 0.05. Observationally, high grade adenomas had higher scores (3 or 4) than low grade ones (P=0.1). Of total 18 patients with stage 3 and/or 4, 14 scored 4 and had cytoplasmic stainning. Conclusions: Our data showed that MACC1 not only can be a prognostic and pathological marker to differentiate high grade from low grade adenoma. 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 3871. doi:10.1158/1538-7445.AM2011-3871