tbuckley/cabot-search huggingface dataset:
Abstract LB-207: Tissue transglutaminase (TG2) - the key driver in inflammation-induced progression of cancer*
Authors: Kapil Mehta, Santosh Kumar, Anupam Kumar
Journal: Cancer Research (2012)

Abstract It is becoming evident that chronic inflammation plays important roles during carcinogenesis, tumor invasion and metastasis. However, molecular mechanisms linking inflammation to cancer progression remains elusive. Here we report that aberrant expression of tissue transglutaminase (TG2), a stress-responsive gene whose expression is modulated by multiple inflammatory signals, plays a key role in reprogramming epithelial cancer cells to dedifferentiation pathway. TG2 expression initiated the developmental program of epithelial to mesenchymal transition (EMT) and conferred stem cell traits in non-transformed and transformed epithelial cells. At molecular level, TG2 expression resulted in constitutive activation of nuclear transcription factor, NF-κB via a non-canonical pathways. Thus, TG2 associates in complex with the inhibitory protein IκBα, resulting in its rapid degradation via non-proteasomal pathway. Hypoxia-induced factor (HIF-1α) was identified as one of the direct downstream targets for TG2-induced NF-κB. TG2/ NF-κB-induced increase in HIF-1α resulted in regulation of transcription repressors like Snail, Zeb-1, and Twist, the known inducers of EMT/CSC. Importantly, our studies suggested that TG2 in closed or compact conformation could promote the oncogenic functions while open or extended conformation is completely inactive in this regard. TG2-induced programming rendered epithelial cells resistant to stress-induced death (including chemo- and radiation-therapies) and increased their propensity to metastasize. Indeed, previous studies support this contention and suggested that inhibition of TG2 could increase the sensitivity of cancer cells to chemotherapy and inhibit their metastasis, both in vitro and in animal models. Moreover, high basal expression of TG2 in breast, ovarian and pancreatic tumor samples is associated with poor disease outcome. These data warrants further studies to develop selective inhibitors/modulators of TG2 to increase the sensitivity of cancer cells to chemotherapy and to prevent their progression to metastatic disease. *Supported by a grant from Susan G. Komen Foundation for Cure. 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-207. doi:1538-7445.AM2012-LB-207
Abstract 2520: Ku-dependent non-homologous end-joining interferes the efficiency of Mre11 binding to replication related DNA double strand breaks
Authors: Hongyan Wang, Xiangming Zhang, Ya Wang
Journal: Cancer Research (2011)

Abstract Background: Camptothecin (CPT), an inhibitor of DNA topoisomerase I, induces replication related DNA double strand breaks (DSBs). Previously, it was reported that Ku-dependent non-homologous end-joining (NHEJ) deficient DT40 cells were more resistant to CPT-induced killing than wild type cells (JBC, 279:37343, 2004), however, the mechanism remains unclear. We were interested in testing the hypothesis that Mre11 binding to DNA double strand break (DSB) (the first step for initiating homologous recombination repair (HRR)) is interfered by the Ku-dependent NHEJ and the interference was much stronger in S phase. Methods: Different fork-related DNA structures were designed for testing the efficiency of purified Mre11 protein (kindly provided by Dr. Tainer) in vitro. DT40 cell lines: wild type, Ku70-/, DNA-PKcs-/-, Rad54-/- and Rad51 conditional knock out cells were used in this study. The efficiency Mre11 binding to chromatin DNA in CPT treated the cell lines were detected. The cell cycle distribution was measured by a flow cytometer. The sensitivity of these cell lines to CPT were measured by a clonogenic assay. Results: Compared with their wild-type counterparts, Rad54−/− and Rad51 conditional knock out cells (essential factors for (HRR)) were much more sensitive to CPT-induced killing but Ku70−/− and DNA-PKcs cells (essential factors for non-homologous end joining (NHEJ)) were much more resistant to CPT-treated killing, which was accompanied by a huge S-phase block in these resistant cells. Mre11 bound to DNA substrates especially to the mimic DNA replication fork substrates. Mre11 bound to chromatin DNA in Ku70-/- and DNA-PKcs-/- cells stronger than that in wild type cells following CPT treatment. Conclusion: CPT-induced S checkpoint facilitates Mre11 binding and promotes HRR, which protects cells from CPT-induced killing. The Ku-dependent NHEJ block efficiency of Mre11 binding to DNA substrates especially DNA replication related structure, which inhibits HRR and renders sensitivity of the cells to CPT treatment. 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 2520. doi:10.1158/1538-7445.AM2011-2520
Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo
Authors: Sorah Yoon, Kai-Wen Huang, Vikash Reebye, Paul Mintz, Yu-Wen Tien, Hong-Shiee Lai, Pål Sætrom, Isabella Reccia, Piotr Swiderski, Brian Armstrong, Agnieszka Jozwiak, Duncan Spalding, Long Jiao, Nagy Habib, John J Rossi
Journal: Molecular Therapy (2016)

The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2'-Fluropyrimidine RNA aptamers (2'F-RNA) - P19 and P1 for construction of a cell type-specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.
Abstract LB-131: Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria.
Authors: Yasuyuki Nakamura, Hiroki Kamino, Hitoya Sano, Hirofumi Arakawa
Journal: Cancer Research (2013)

Abstract The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. However, when MALM is inhibited, Mieap induces vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulf and degrade the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impairs both MALM and MIV generation. These results suggest that Mieap plays a pivotal role in mitochondrial quality control by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect. Citation Format: Yasuyuki Nakamura, Hiroki Kamino, Hitoya Sano, Hirofumi Arakawa. Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. [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 LB-131. doi:10.1158/1538-7445.AM2013-LB-131
Abstract 124: Involvement of the notch pathway in the clonogenicity of human multiple myeloma cell lines
Authors: David Chiron, Martine Amiot, Jerome Moreaux, Bernard Klein, Catherine Pellat-Deceunynck
Journal: Cancer Research (2010)

Abstract Multiple Myeloma (MM) is a fatal plasma cell malignancy characterized by deregulation of both proliferation and cell-death. Using a collagen based (serum-free) semi-solid assay, we have evaluated the ability of 40 HMCL to form colonies either spontaneously or in the presence of exogenous growth factors (IL6 or IGF-1). We have shown that 28 Human Myeloma Cell Lines (HMCL) formed colonies in the presence of exogenous IL6, 14 in the presence of exogenous IGF-1 and 12 have the capacity to clone spontaneously without any growth factor. In the present study, we have addressed: 1) Autocrine growth factors implicated in the spontaneous clonogenicity 2) Gene expression profile (GEP) associated with the spontaneous clonogenicity On the one hand, we showed that IGF-1 or SCF (CD117) autocrine loop supports the growth of 5 and 1 HMCL, respectively. On the other hand, GEP analysis of 40 HMCLs revealed that jagged2 gene expression is statistically associated with the spontaneous clonogenicity. Fourteen cell lines express jagged2, among them 11 formed colonies spontaneously. To confirm this correlation, we next determined JAGGED2 expression by Western-blot and showed that only spontaneous clonogenic HMCL highly expressed this protein. JAGGED2 is a ligand of NOTCH1 and NOTCH2 receptors that also appear to be highly expressed on MM cells (Western-blot and Flow-cytometry). Overexpression of JAGGED2 in MM was reported either to be induced by hypomethylation of jagged2 promoter or by a lack of expression of the repressor SMRT/NCoR2. However, these mechanisms are not associated with JAGGED2 expression in our 14 JAGGED2+ HMCLs, suggesting another mechanism(s) currently under investigation. Of note, jagged2 is expressed by 40% of MM patients (as documented by RT-PCR) and thus is not restricted to HMCL. To address the involvement of Notch pathway in the spontaneous clonogenicity of myeloma cells, we generated sh-JAGGED2 HMCL using lentiviral systems. We observed that this stable down-regulation fully abrogates spontaneous clonogenic capacity. To further analyze the implied mechanism(s), we used a low-cellular-density liquid culture (serum-free, cytokine-free) to mimic our collagen-based assay. In this model, stable down-regulation of JAGGED2 induces inhibition of proliferation followed by delayed cell death. The molecular mechanism implicated in this process is currently under investigation. Our results highlight a subgroup of JAGGED2 positive HMCLs that display spontaneous clonogenic capability. Furthermore, we described a new implication of JAGGED2/NOTCH pathway in survival and proliferation of myeloma cells under stringent conditions such as collagen-based clonogenic assay. 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 124.
PTU-214 An in-vitro study to assess, and improve, the accuracy of colonic polyp sizing among nurse endoscopists, trainees and consultant gastroenterologists
Authors: J Geraghty, Z Raisi-Estabragh, M Gillon, P O'Toole, S Sarkar
Journal: Gut (2012)

<h3>Introduction</h3> Knowing if polyps are larger than 10mm is critical when determining colonoscopic surveillance strategies. Judging polyp size from the endoscopic view alone becomes important if polyps are not retrieved intact. Strategies based on deliberately discarding small polyps rely on accurate discrimination of polyp size but little is known about endoscopists ability to make this judgement. Our aim is to assess the accuracy of polyp size estimation using a novel in vitro model, comparing different professional groups and use of accessories to improve estimates. <h3>Methods</h3> Nine endoscopists (3 consultants, 3 trainees and 3 nurse endoscopists) judged the size of 15 “polyps” made from modelling clay (size range 6–36 mm) placed inside a colonoscopy training model (Koken Co Ltd, Tokyo). Polyps of different sizes were presented in random order. Size estimates were made using endoscopic visual assessment alone or by comparing the polyp to biopsy forceps or a 10 mm snare. A degree of confidence for each guess was recorded. <h3>Results</h3> Consultants and trainees were significantly better than nurse endoscopists at judging whether the model polyps were larger or smaller than 10 mm (91.8% vs 79.2% p&lt;0.05). Overall, visual assessment alone had an accuracy of 78.8%. Inaccuracy was largely due to underestimation of size. Use of accessories improved discrimination around the 10 mm threshold (p&lt;0.05). The snare produced slightly better accuracy (87.9%) than forceps (83.8%) (NS). All professional groups expressed similar degrees of confidence in their estimates. <h3>Conclusion</h3> In this model, medical endoscopists were better than nurse endoscopists in assessing the size of polyps. This may be because nurses in our study do not routinely perform polypectomy whereas doctors have all had the opportunity to learn from comparing the size of resected polyps with their original endoscopic assessment. Use of biopsy forceps or a snare improved size estimation and these may be helpful tools when teaching this important aspect of polyp assessment in vivo. <h3>Competing interests</h3> J Geraghty Grant/Research Support from: Cook Medical, Z Raisi-Estabragh: None declared, M Gillon: None declared, P O9Toole: None declared, S Sarkar: None declared.
THU0347 Central Blood Pressure in Patients with Ankylosing Spondylitis
Authors: N. Karoli, A. Rebrov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Central (aortic) blood pressure (BP), which is the pressure exerted on the heart and brain, may be different from the pressure that is measured at the arm. Clinical studies have indicated that central BP may have predictive value independent of the corresponding peripheral (brachial) BP. <h3>Objectives</h3> To study the central and peripheral BP in patients with <b>ankylosing spondylitis</b> (AS). <h3>Methods</h3> 78 patients (6 female and 72 male, mean age ± SD 42,71±9.95 years) with reliable diagnosis of AS and without clinically-evident atherosclerosis were included. Diagnosis of AS were made according to the modified New York criteria. Duration of disease was 15.41±9.01 years. Control group consisted of 38 healthy age-matched volunteers. Central blood pressure (SBPao) was measured using TensioMed Arteriograph (TensioMed, Hungary). <h3>Results</h3> We noted non-significantly increased central systolic BP in patients with AS compared controls group (123,2±23.09 vs. 115.66±13.73 mmHg; P=0.06). In healthy subjects differences between central and peripheral BP was -10.34±8.19 mm Hg, in patients with AS -7.24±6.96 mm Hg (p&lt;0.05). In 17.9% patients with AS peripheral BP was higher than central BP (DBP &gt;0), in all control subjects central BP was higher than peripheral (p&lt;0.001). We study index CP =(SBPao/brachial systolic BP)×100. In patients with AS it was 94.2±5.19 mm Hg, in controls patient 91.81±6.39 mm Hg (p&lt;0.05). Patients with AS and control group subjects was not differences by systolic BP, diastolic BP, pulse and mean BP. We noted correlations between SBPao and age (r=0,23 p&lt;0,05), total cholesterol (r=0.37, p&lt;0.01), left ventricular mass by echocardiography (r=0.39, p&lt;0.01), carotid and brachial wall (r=0.69, p&lt;0.01 and r=0.68, p&lt;0.01). Also we noted correlations between SBPao and brachial augmentation index (Aix) (r=0,47, p&lt;0,01), aortal Aix (r=0,56, p&lt;0,001), pulse wave velocity (r=0,52, p&lt;0,001). In control group this correlations we didn`t notified. <h3>Conclusions</h3> The late systolic augmentation of the central pressure waveform is associated with an increase in left ventricular mass index independent of age and mean BP and carotid systolic BP is an independent determinant of left ventricular wall thickness. Moreover, central pressure is also more closely related to other important cardiovascular intermediate end points, such as vascular hypertrophy, extent of carotid atherosclerosis than brachial pressure.<b>We</b> noted significantly increased central BP and decreased dissociation between central and brachial BP in patients with AS compared with healthy persons. <h3>Disclosure of Interest</h3> None Declared
Prognostic Significance of FDG PET/CT on the Follow-Up of Patients of Differentiated Thyroid Carcinoma With Negative 131I Whole-Body Scan and Elevated Thyroglobulin Levels
Authors: Gulin Ucmak Vural, Burcu Esen Akkas, Nur Ercakmak, Sandip Basu, Abass Alavi
Journal: Clinical Nuclear Medicine (2012)

Aims This study aimed (a) to determine the clinical and histopathologic factors that are related to FDG avidity in the recurrence/metastases of patients with differentiated thyroid carcinoma (DTC) who present with elevated thyroglobulin (Tg) levels and negative 131I whole-body scans (WBSs), (b) to clarify Tg cutoff levels in this setting, and (c) to evaluate the impact of PET/CT on patient management strategies and hence to critically look into the importance of PET/CT in combination with Tg in clinical decision making. Methods A total of 105 patients with DTC with negative 131I WBS and neck ultrasound but elevated Tg, who underwent FDG PET/CT for the suspicion of recurrent/metastatic disease, were included in this analysis. All patients had previously undergone total thyroidectomy and radioiodine ablation/therapy. PET/CT results were correlated with Tg levels and clinical and histopathologic characteristics of the primary tumor compared with the follow-up data. Results PET/CT was true-positive in 69 patients (of which 23 had surgically amenable disease), true-negative in 20, false-positive in 6 patients and false-negative in 10 patients. Extrathyroidal spread was an independent risk factor related to FDG-avid recurrence. Tumor size was significantly higher in PET-positive patients than others, 2.25 (1.8) versus 1.5 (1.1) cm, P = 0.02. Significant correlation was observed between PET positivity and high Tg levels (P = 0.0001). Receiver operating characteristic curve analysis demonstrated a Tg cutoff of 1.9 ng/mL under thyroid-stimulating hormone suppression, 38.2 ng/mL with thyroid-stimulating hormone stimulation. Among PET-negative patients, no recurrence was detected in patients with undetectable/suppressible Tg in on-therapy state. Conclusions PET positivity correlated with extrathyroidal spread, and elevated Tg in recurrent/metastatic DTC. FDG PET/CT in combination with Tg levels was crucial in defining management strategies in patients with DTC with negative 131I WBS. A negative FDG PET/CT scan predicts a favorable prognosis and lack of recurrence on follow-up in patients with “suppressible Tg” levels in the on-therapy state despite significant elevation of Tg in the off-therapy state.
Efficacy and Safety of Imprime Pgg, a Novel Innate Immune Modulator, in Combination with Bevacizumab (BEV), Carboplatin and Paclitaxel for the 1St-Line Treatment of Stage Iv Nsclc
Authors: A. Braun, W. Engel-Riedel, F. Schneller, M. Wolf, W. Schuette, J. Lowe, P. Mattson, M. Gargano, M. Patchen, R. Huhn
Journal: Annals of Oncology (2015)
Abstract 2979: Epithelial-mesenchymal gene expression signature defines clinically relevant subtypes in epithelial ovarian cancer
Authors: Ruby YJ Huang, Tuan Zea Tan, Meng Kang Wong, Noriomi Matsumura, Hung Cheng Lai, Vin Yee Chung, Jieru Ye, Seiichi Mori, Jean Paul Thiery
Journal: Cancer Research (2012)

Abstract Epithelial ovarian cancer (EOC) represents a broad and heterogeneous entity which includes different invasive behavior as well as distinct histopathological subtypes. The heterogeneity of EOC is further complicated by the fact that EOC is characterized by a high degree of genetic damages and multiple genetic alterations resulting from different mechanisms. Even within the seemingly similar histo-pathological group, molecular subtypes with different gene/pathway activations have been identified. In this study, we described a classification scheme based on in silico meta-analysis of gene expression profiling of 1,538 EOC microarray data. and identified five major robust subtypes termed Epithelial-A, Epithelial-B, Mesenchymal, Stem-A, and Stem-B that were distinctive in gene expression patterns. The epithelial subtype is hallmarked by genes known to confer epithelial characteristics, such as Keratin genes (KRT17, 14, 19, and 7), E-cadherin (CDH1), and Ep-CAM (EPCAM) and show the second best prognosis in Kaplan-Meier analysis. On the other hand, the mesenchymal subtype consists of genes such as fibronectin (FN1) and known EMT inducers ZEB1 and TWIST1. The Stem-A subtype consists of genes which confer stemness (LGR5, NCAM1). The Mesenchymal and Stem-A subtypes are linked with poorer outcomes. We further utilized a panel of 42 ovarian cancer cell lines to model EMT in vitro by performing phenotypic EMT characterization. Four EMT subgroups (epithelial, intermediate epithelial, intermediate mesenchymal, mesenchymal) representing different epithelial-mesenchymal compositions on the EMT spectrum were identified. We also demonstrated that this EMT spectrum can be used to refine the analysis of data generated in cell-based functional studies. By performing EMT-related functional assays, we found that ovarian cancer cells harbouring intermediate phenotypes are more migratory, invasive, anoikis resistant, and more spheroidogenic. We further utilized this cell line model to apply a cell line-based EMT scoring system to re-classify the 1,538 EOC microarray data. It revealed that the Mesenchymal and Stem-A subtypes were both enriched in higher mesenchymal scores. This supported the hypothesis of EMT's contribution to the aggressiveness of solid tumors. In conclusion, our results showed that EOC is sub-classified into distinct molecular subtypes correlated with clinical outcomes that are linked to EMT. 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 2979. doi:1538-7445.AM2012-2979