tbuckley/cabot-search huggingface dataset:
Abstract 1686: Glypican-3 (GPC3) induces a mesenchymal-epithelial transition in human breast cancer cells lines
Authors: Lilian F. Castillo, Rocio Tascon, Elisa Bal de Kier Joffe, Giselle Peters
Journal: Cancer Research (2016)

Abstract Glypicans constitute a family of heparan sulphate proteoglycans which are linked to the extracellular surface of the plasma membrane through a glycosylphosphatidylinositol anchor. Since GPC3 has been linked to cancer, herein we generated and characterized a pre-clinical human breast cancer cell model to evaluate the role of GPC3 in human mammary tumor progression. GPC3 expression was blocked in MCF-7 cells (poorly-metastatic, GPC3 +) by siRNA (generating MCF-7-shGPC3 sublines), while it was overexpressed in MDA-MB231cells (metastatic, GPC3 -) by viral infection (producing MDA-MB231-GPC3 sublines). We performed in vitro and in vivo characterization of this model. GPC3 silenced MCF-7 cells acquired F-actin stress fibers, enhanced their clonogenic ability (Colony number 130 -shGPC3 vs. 37 -sh Negative Control (NC)) as well as their migration (Wound coverage (%): 15 -shGPC3 vs. 2 -shNC), were less susceptible to cell death induction (Cell death (%): 21.6 -shGPC3 vs. 34 -shNC), diminished the expression of the epithelial marker E-Cadherin while acquired the mesenchymal marker N-Cadherin, and were more invasive and metastatic in vivo. These cells exhibited an upregulation of the EMT-transcription factor ZEB1, and the canonical Wnt/beta-Catenin signaling pathway was activated. GPC3 overexpressing MDA-MB231 cells misplaced their fibroblast-like appearance as well as their F-actin stress fibers, repressed their clonogenicity (Colony number: 8 -GPC3 vs. 40 -vector) and migratory capacity (Wound coverage (%): 10 -GPC3 vs. 90 -vector), were more sensitive to death in starving condition (Cell death (%) 30 -GPC3 vs. 6.5 -vector), got the ability to form E-Cadherin dependent-spheroids, reexpressed E-Cadherin in cell-cell junctions and downregulated the mesenchymal markers N-Cadherin and vimentin, while were less invasive and metastatic in vivo. The expression of the E-Cadherin repressor ZEB1 was diminished, as well as the activity of the canonical Wnt/beta-Catenin signaling pathway. However, when canonical Wnt signaling was activated by LiCl, the expression of E-Cadherin did not change. In summary, we present in vitro and in vivo experimental evidence supporting the hypothesis that GPC3 has a protective role of human breast cancer progression by inducing mesenchymal-epithelial transition (MET). The canonical Wnt/beta-Catenin signaling inhibition would not be required for MET process induced by GPC3. Citation Format: Lilian F. Castillo, Rocio Tascon, Elisa Bal de Kier Joffe, Giselle Peters. Glypican-3 (GPC3) induces a mesenchymal-epithelial transition in human breast cancer cells lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1686.
Desialylation: A Novel Platelet Clearance Mechanism and a Potential New Therapeutic Target in Anti-GPIb Antibody Mediated Thrombocytopenia
Authors: Dianne E. van Der Wal, Guangheng Zhu, June Li, Brian Vadasz, Yougbare Issaka, Sean Lang, John Freedman, Heyu Ni
Journal: Blood (2012)
Growth differentiation factor 15 (GDF-15) as potential serum biomarkers in patients with metastatic colorectal cancer.
Authors: Michal Vocka, Daniel Langer, Jaromir Petrtyl, Marta Kalousova, Tomas Zima, Tomas Hanus, Lubos B. Petruzelka
Journal: Journal of Clinical Oncology (2016)

e15098 Background: The novel inflammatory mediator growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1, is a cytokine member of the transforming growth factor beta family. Previous study identified GDF15 as the potential biomarker of lymph node metastasis in colorectal cancer (CRC) and as candidate biomarker for CRC diagnosis, which may be related to liver metastasis. The aim of this study was an investigation of GDF-15 as an effective serum biomarker in metastatic CRC and its potential prognostic value. Methods: Between November 2011 and May 2013, we collected serum samples from 79 healthy controls and 97 patients with metastatic colorectal cancer at the time of diagnosis or at progression. Serum levels of GDF-15, CEA and CA19-9 were measured by ELISA. (GDF-15), also known as macrophage inhibitory cytokine-1, is a cytokine member of the transforming growth factor beta family. Previous study identified GDF15 as the potential biomarker of lymph node metastasis in colorectal cancer (CRC) and as candidate biomarker for CRC diagnosis, which may be related to liver metastasis. The aim of this study was an investigation of GDF-15 as an effective serum biomarker in metastatic CRC and its potential prognostic value. Results: Serum GDF-15 levels were significantly higher in patients with colorectal cancer compared to healthy controls (p < 0.0001). GDF-15 had (with same specificity) same sensitivity compared to CEA and better sensitivity compared to CA19-9. Moreover in contrast to CEA, serum levels of GDF-15 correlated with extent of liver involvement (p < 0.0001) and presence of primary tumor or local relapse (p < 0.0001). Patients with normal GDF-15 levels had significantly better survival compared to patients with higher GDF-15 levels (21.3 vs 5.7 months; p < 0.0001). Conclusions: Our results indicate that GDF-15 is an effective biomarker in patients with metastatic colorectal cancer with better sensitivity than CA19-9 and same sensitivity as CEA. GDF-15 levels strongly correlate with extension of liver disease, presence of colon involvement and seem to have prognostic value.
Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer
Authors: M. M. Bertagnolli, C. C. Compton, D. Niedzwiecki, R. S. Warren, S. Jewell, G. P. Bailey, R. J. Mayer, R. Goldberg, L. Saltz, M. Redston
Journal: Journal of Clinical Oncology (2006)

10003 Background: Colon cancers exhibiting a high level of microsatellite instability (MSI-H) show distinct clinicopathological features, including both better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. We investigated the impact of adjuvant chemotherapy containing irinotecan in patients with MSI-H colon cancers. Methods: CALGB protocol 89803 randomized 1264 patients with resected stage III colon cancer to receive post-operative 5-FU and leucovorin (LV) with or without irinotecan. Paraffin blocks containing primary tumor and normal tissue were collected. Microsatellite instablility was assessed using a panel of mono- and di-nucleotide markers. Disease free survival (DFS) was measured from trial entry until documented disease progression or death from any cause. A statistical significance level of 0.2 was used in screening to generate hypotheses regarding MSI status and outcome. Median follow-up at analysis was 3.8 years. Overall C89803 showed no advantage for addition of irinotecan to 5-FU/LV. Results: Patients with and without tumor samples analyzed did not differ by treatment, age, gender, primary site, T-stage, differentiation, # positive nodes, or mucinous type. Of 482 tumors analyzed, 75 (16%) demonstrated MSI-H. MSI-H cancers were more likely to be located in the proximal colon (p&lt;0.0001), of high histologic grade (p&lt;0.0001) and mucinous histology (p&lt;0.0001), and also had increased numbers of tumor-containing lymph nodes (mean # positive nodes/case = 3.5 for MSI Low/Stable vs. 4.7 for MSI-H; p = 0.04). At the time of analysis 143 of 482 patients (36%) analyzed experienced tumor recurrence and/or death due to any cause. For patients with MSI-H tumors, DFS was better in those treated with irinotecan in addition to 5-FU/LV (logrank p=0.18). Among patients with MSI Low/Stable tumors there was no difference in DFS between those treated with and without irinotecan (logrank p =0.39). Conclusions: Early results from CALGB protocol 89803 indicate that addition of postoperative irinotecan to 5-FU/LV may improve DFS in patients with stage III colon cancers that exhibit MSI-H. Longer follow-up is required to confirm this finding. [Table: see text]
Abstract 4593: Analysis of transforming growth factor β receptor trafficking on different signaling transduction pathways
Authors: Evelyn Ng, John Di Guglielmo
Journal: Cancer Research (2016)

Abstract Transforming growth factor beta (TGFβ) is a cytokine that regulates cellular adhesion, proliferation and apoptosis. Its canonical downstream effectors include receptor-regulated Smad2/3 proteins, which are phosphorylated and then translocated to the nucleus to alter transcription. Additionally, other atypical pathways are simultaneously initiated by TGFβ, including that of p38 (a mitogen activated protein kinase). TGFβ acts as a tumour suppressor in its normal epithelial environment, but in tumor cells, it promotes epithelial-mesenchymal transition and cell migration. The manner in which tumor cells overcome the growth suppressive effects of TGFβ is not well-understood, especially since downstream TGFβ signaling is still apparent in these cells. This may point to selective pathway activation as a reason for its dual roles. Thus, it is important to consider membrane trafficking—a central process that directs signaling between various cascades. Previous studies from our lab demonstrate that perturbation of aPKC signaling alters TGFβ receptor trafficking and Smad signal transduction. Furthermore, we have also observed increased access to the p38 MAPK pathway in cells that have been silenced for aPKC expression. We are currently assessing the trafficking of the TGFβ receptor complex in order to investigate the mechanism(s) responsible differential access to specific signaling pathways. This will be addressed using techniques such as co-immunoprecipitation, immunofluorescence microscopy, subcellular fractionation and western blotting. Determining these mechanisms will further our understanding on cancerous TGFβ pathway regulation, and may lead to the discovery of promising therapeutic targets. Citation Format: Evelyn Ng, John Di Guglielmo. Analysis of transforming growth factor β receptor trafficking on different signaling transduction pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4593.
Abstract 2889: Loss of 4E-BP1 function promotes EMT and metastasis via translational activation of snail
Authors: Qing Ye, Weijia Cai, Qing-Bai She
Journal: Cancer Research (2016)

Abstract The cap-dependent translation is frequently deregulated in a variety of cancers associated with tumor progression. However, the molecular mechanisms underlying the translational activation for cancer metastatic progression remains largely elusive. Here, we demonstrate that activation of cap-dependent translation by silencing the translational repressor 4E-BP1 causes cancer epithelial cells to undergo epithelial-mesenchymal transition (EMT), which is associated with selective upregulation of the EMT inducer snail followed by repression of E-cadherin expression and promotion of cell migration and invasion as well as metastasis. Conversely, inhibition of cap-dependent translation by a dominant active mutant 4E-BP1 effectively downregulates snail expression and inhibits cell migratory/invasive capacities and metastasis. Furthermore, dephosphorylation of 4E-BP1 by mTORC1 inhibition or directly targeting the eIF4F translation initiation also profoundly attenuates snail translation/expression and cell motility, whereas knockdown of 4E-BP1 or overexpression of snail significantly rescues the inhibitory effects. Importantly, 4E-BP1-regulated snail expression is not associated with its changes in the level of transcription or protein stability. Together, these findings reveal a novel role of 4E-BP1 in the regulation of EMT and metastasis through translational control of snail expression and activity, and suggest that targeting cap-dependent translation may provide a promising approach for blocking snail-mediated metastatic potential of cancer. Citation Format: Qing Ye, Weijia Cai, Qing-Bai She. Loss of 4E-BP1 function promotes EMT and metastasis via translational activation of snail. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2889.
Abstract 4683: Verapamil and tamoxifen modulate ABCB1 expression in multidrug-resistant cells and resensitize them to conventional chemotherapy
Authors: Georgia Limniatis, Elias Georges
Journal: Cancer Research (2016)

Abstract Multidrug-resistant (MDR) tumors are an increasingly important obstacle in cancer treatment, wherein many cases are associated with the overexpression of P-glycoprotein 1 (P-gp1, ABCB1). Previous efforts to sensitize ABCB1-expressing tumor cells to anti-cancer drugs were associated with severe side effects, so interest in clinical trials using these drugs has dwindled. Studies have shown P-glycoprotein-overexpressing cells to be hyper sensitive (or collaterally sensitive) to a diverse group of non-toxic compounds. Given earlier results demonstrating a significant increase in ABCB1 expression post-chemotherapeutic treatment of cancer patients (e.g., breast, ovarian, myeloma, and acute myeloid leukemia), and the role of ABCB1 in drug resistance, it was determined that targeting ABCB1-expressing tumor cells with effective collateral sensitivity drugs should increase the effectiveness of current chemotherapeutic treatments. In this report, it was of interest to determine the effect of the collateral sensitivity drugs verapamil and tamoxifen on P-glycoprotein 1 expression at the level of cells and individual cell clones. Clones from P-gp1-overexpressing Chinese hamster ovarian cell lines (CHRC5) or triple negative breast cancer cells (MDA-MB-231/400 nM doxo) were treated with varying levels of collateral sensitivity drugs and ABCB1 expression was determined by Western blots and ELISAs. The sensitivity of each cell clone to anti-cancer or collateral sensitivity drugs was determined using cytotoxicity assays. Our results demonstrate a drop in ABCB1 expression in each clone, together with decreased collateral sensitivity and overall increased sensitivity to anti-cancer drugs in cell lines selected with verapamil and tamoxifen. Work is in progress to study the various mechanisms responsible for this drop in ABCB1 expression and its impact on treatment outcome. Citation Format: Georgia Limniatis, Elias Georges. Verapamil and tamoxifen modulate ABCB1 expression in multidrug-resistant cells and resensitize them to conventional chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4683.
Measuring subjective improvement of palliative chemotherapy in women with platinum-resistant or -refractory ovarian cancer: The symptom benefit study (ANZGOG-0701/ GCIG/PoCoG).
Authors: Michael Friedlander, Martin R. Stockler, Phyllis Noemi Butow, Amit M. Oza, Rachel O'Connell, Julie Martyn, Kim Gillies, Katrin Marie Sjoquist, Madeleine King
Journal: Journal of Clinical Oncology (2014)

TPS5615 Background: The objective of chemotherapy in women with platinum resistant recurrent ovarian cancer is symptom palliation. Response rates or time to progression are used to assess "clinical benefit", but fail to incorporate subjective benefit. There is international consensus that a valid measure of subjective symptom benefit is required. The aims of Stage 2 of this study are to assess the validity, reliability and statistical efficiency of a new patient-reported outcome measure, the Measure of Ovarian Symptoms and Treatment concerns (MOST, developed in Stage 1), relative to the best candidate scales of existing ovarian cancer specific quality of life measures (QLQ-C30/OV28, FACT-O/FOSI), develop criteria for defining subjective symptom benefit, determine how many women have subjective benefit with palliative chemotherapy and develop a prognostic model to better predict benefit, time to progression and survival in this heterogeneous group of patients. Methods: Prospective observational cohort study in women with platinum resistant or refractory recurrent ovarian cancer who are about to commence palliative chemotherapy. Changes in perceived ovarian cancer symptoms are assessed from baseline to post treatment using QLQ-C30/OV28, FACT-O/FOSI and MOST. Eligibility: Women with platinum resistant/refractory epithelial ovarian, primary peritoneal or fallopian tube cancer with life expectancy > 3 months and ECOG PS 0-3 who are about to start palliative (2nd or subsequent line) chemotherapy. Trial status: Stage 2 opened in Feb 2011 with a target recruitment of 750 patients. To date 623 patients have been recruited from Australia, New Zealand, Ireland, Germany and Italy, Canada, the UK, the US, France, Sweden, Norway and Japan. Summary: This study will identify the most statistically efficient measure of subjective symptom benefit of palliative chemotherapy for use in endpoint analysis in clinical trials. Ultimately, it will help physicians and patients make more informed decisions regarding treatment options based on the likelihood of benefit and their potential impact on symptom control and improved quality of life. Clinical trial information: ACTRN12607000603415.
Dopamine beta-hydroxylase inhibition in a patient with Wilson's disease and manic symptoms
Authors: R S Pandey, K N Sreenivas, N M Patil, H S Swamy
Journal: American Journal of Psychiatry (1981)

The authors studied the effect of dopamine beta-hydroxylase inhibition on the manic symptoms of a 34-year-old man. They found that fusaric acid decreased the patient's manic symptoms and that his symptoms approximately reverted to their previous state when a placebo was reinstituted.
Abstract 4016: Personalizing the synergy of focal radiation and immunotherapy
Authors: Jan Poleszczuk, Kimberly Luddy, Shari Pilon-Thomas, Jonathan Schoenfeld, Heiko Enderling
Journal: Cancer Research (2016)

Abstract Tumors grow within a host tissue that both facilitates progression by supplying nutrients and growth factors, and inhibits it through physical constraints and immune surveillance. Transformed cancer cells are confronted with this innate and adaptive immune surveillance, and tumors that develop to become clinically apparent have evolved to evade the immune system. This complex ecological system may be tipped back in favor of effective immune surveillance and tumor regression through novel immunotherapeutic strategies, particularly when used in concert with focal cytotoxic agents such as radiotherapy. We developed a multi-scale mathematical model framework to simulate local tumor-immune interactions as well as systemic distribution patterns of T cells activated locally in each metastatic site. We simulate focal radiotherapy-induced cytotoxicity and subsequent activation of an adaptive immune response, which may propagate systemically to cause regression of unirradiated metastases, known as the abscopal effect. We simulate concurrent anti-CTLA4 immunotherapy to investigate synergy. Model simulations suggest that systemic distribution of locally activated T cells is dependent on (i) the anatomical distribution of metastatic sites, (ii) the tumor volume of each metastasis, (iii) the site of focal therapy, (iv) the local therapy protocol of immune activation, and (v) the timing of concurrent immunotherapy. We find that irradiation of different metastatic sites has different likelihoods of inducing systemic tumor regressions. The developed framework can identify combination therapy protocols that optimally harness the synergy of focal therapy-induced immunity with immunotherapy, and identify optimum treatment targets on a per patient basis. Citation Format: Jan Poleszczuk, Kimberly Luddy, Shari Pilon-Thomas, Jonathan Schoenfeld, Heiko Enderling. Personalizing the synergy of focal radiation and immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4016.
Abstract 4460: Precision cancer risk diagnosis by accumulation of epigenetic alterations
Authors: Toshikazu Ushijima, Kiyoshi Asada, Masahiro Maeda, Takeshi Nakajima, Taichi Shimazu
Journal: Cancer Research (2016)

Abstract Background and Aim: Aberrant DNA methylation is induced by chronic inflammation, and can be accumulated in normal-appearing tissues [reviewed in Ushijima and Hattori, Clin Cancer Res, 2:143, 2012]. Cross-sectional studies have shown that the degree of accumulation of aberrant DNA methylation was correlated with cancer risk, especially inflammation-associated cancers. In this study, we aimed to demonstrate that cancer risk can be predicted by an epigenetic cancer risk marker by a multicenter prospective cohort study. Methods: We enrolled 826 patients with early gastric cancer, aged 40-80 years, who had undergone endoscopic resection. If a patient had active Helicobacter pylori (H. pylori) infection, the patient was enrolled after eradication of H. pylori. At the time of enrollment, one gastric biopsy was taken, and methylation levels of three preselected genes, miR-124a-3, EMX1 and NKX6-1, were measured by quantitative methylation-specific PCR. The patients were followed up annually by endoscopy to detect metachronous gastric cancer. To exclude cancers undetected at the time of enrollment, “authentic” metachronous gastric cancers were defined as those developed 1 year after enrollment. Results: With a median follow-up of 2.97 years, 782 of 826 patients had at least one follow-up. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1-2, 2-3 and ≥3 years after the enrollment, respectively. The highest quartile of the miR-124a-3 methylation level had a significantly high HR in univariate analysis (95% CI) [2.17 (1.07 - 4.41); p = 0.032] and adjusted HR in multivariate analysis [2.30 (1.03 - 5.10); p = 0.042] [Asada et al, Gut, 64:388, 2015]. More importantly, with a median follow-up of 4.84 years, a multivariate analysis yielded a larger HR [2.79 (1.34 - 5.81)] with a smaller p value (0.0061). Conclusions: This study, for the first time, demonstrated the usefulness of an epigenetic cancer risk marker by a multicenter prospective cohort study. DNA methylation accumulated in normal-appearing tissues was considered to be highly useful for precision cancer risk diagnosis. Citation Format: Toshikazu Ushijima, Kiyoshi Asada, Masahiro Maeda, Takeshi Nakajima, Taichi Shimazu. Precision cancer risk diagnosis by accumulation of epigenetic alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4460.