tbuckley/cabot-search huggingface dataset:
Abstract 5181: KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer
Authors: Ke-Fan Pan, Ming-Hsien Chien, Wei-Jiunn Lee, Michael Hsiao, Kuo-Tai Hua
Journal: Cancer Research (2018)

Abstract KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3′UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3′UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes Citation Format: Ke-Fan Pan, Ming-Hsien Chien, Wei-Jiunn Lee, Michael Hsiao, Kuo-Tai Hua. KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5181.
GENE-03. SERUM LONG NONCODING RNA HOTAIR AS NOVEL DIAGNOSTIC AND PROGNOSTIC BIOMARKER IN GLIOBLASTOMA MULTIFORME
Authors: Sze Kiat Tan, Chiara Pastori, Clara Penas, Jann Sarkaria, Ricardo J Komotar, Nagi Ayad
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most common malignant adult brain tumor. However, detecting tumor progression via MRI is often inconclusive which can lead to delayed treatment. Therefore, there is an urgent need to develop a peripheral biomarker for GBM. Utilizing single molecule sequencing, we have previously demonstrated that hundreds of long noncoding RNAs, including HOTAIR, are strongly dysregulated in GBM and HOTAIR is critical in GBM cells proliferation. The purpose of this study was to investigate the prognostic and diagnostic values of serum HOTAIR in GBM. The HOTAIR expressions were measured in 32 GBM serum samples and 40 healthy controls using qRT-PCR. The PCR products were subsequently subcloned into pCRTM4-TOPO®TA vectors for DNA sequencing. A ROC curve was generated to examine HOTAIR’s prognostic value and correlations of serum HOTAIR levels with clinicopathological features were analyzed. Serum exosomes were also isolated and validated by Western blot and NanoSight analysis. We further detected serum HOTAIR levels in mice with GBM PDX-39 tumors implanted intracranially. GBM patients had a significantly higher serum HOTAIR expression than those of healthy controls (P<0.0001, Mann-Whitney test). At the cut-off value of 5297 HOTAIR level in serum, the area under the ROC curve distinguishing GBM patients from normal controls was 0.776 (95% CI: 0.664–0.888, P<0.0001), with 81.3% sensitivity and 72.2% specificity. In addition, Pearson correlation analysis indicated a medium correlation of serum HOTAIR levels and the corresponding tumor HOTAIR levels (r=0.734, P<0.01). Clinical data also indicated that HOTAIR was correlated with higher WHO grades of glioma. HOTAIR was found to be enriched in exosome fraction of GBM serum. Moreover, the presence of GBM tumor in mice lead to significant increase in serum HOTAIR expression. Our results, for the first time, demonstrated that the serum HOTAIR could be used as a novel biomarker for diagnosis and prognosis in GBM.
Abstract 13596: Neuronal Nitric Oxide Synthase Function is Impaired in Human Hypertension: Effects of Sildenafil
Authors: Sitara GKhan, HusainShabeeh, HenryFok, SallyBrett, Ajay MShah, PhilChowienczyk
Journal: Circulation (2013)

Introduction: Neuronal nitric oxide synthase (nNOS) plays a key role in regulating microvascular tone in healthy man at rest and during mental stress, but its function in hypertension is unknown. We hypothesized that basal release of nitric oxide from nNOS at rest and during mental stress is impaired in subjects with essential hypertension, and phosphodiesterase type 5 (PDE5) inhibition will improve nNOS mediated responses. Methods: 14 hypertensive subjects (mean±SD age 39.6±13.5 years, BP 141±13/87.8±11 mmHg) and 14 normotensive controls matched for age, BMI and cholesterol (age 31.3±8.9 years, BP 121±6.6/77±6.9mmHg) participated in a single blinded 2-phase cross-over study receiving placebo and 50mg p.o. sildenafil 1 hour before forearm blood flow (FBF) studies. Strain gauge plethysmography was used to measure FBF in both arms, the right arm acting as control. The left brachial artery was cannulated for infusion of the selective nNOS inhibitor S-methyl-L-thiocitrulline (SMTC). FBF was measured at baseli...
Radiofrequency Catheter Ablation of Atrial Flutter
Authors: HervePoty, NadirSaoudi, MohanNair, FredericAnselme, BriceLetac
Journal: Circulation (1996)

Background Radiofrequency ablation of type 1 atrial flutter (AFl) has recently evolved toward an anatomically guided procedure directed to isthmuses at the lower part of the right atrium (RA). However, different types of block at these isthmuses may be observed and potentially correlated with different late outcomes. In addition, because the ablation is anatomically guided, ablation should be possible during sinus rhythm. Methods and Results Forty-four patients underwent ablation of type 1 AFl performed during ongoing tachycardia (33 patients) or sinus rhythm (11 patients). Evidence of inferior vena cava–tricuspid annulus isthmus block was assessed by changes in RA impulse propagation while pacing from both sides of the ablation site. Apparent complete isthmus block was achieved in 43 of 44 patients with 9±7 pulses. However, incomplete block mimicking complete block because of intra-atrial conduction delay but leading to a different low RA activation pattern was individualized. At the end of the procedure...
Abstract 20369: Hearts of Early Adolescent Pediatric Donors can be safely used in Adults
Authors: ShivankMadan, Snehal RPatel, DanielSims, OmarSaeed, JooyoungShin, DanielGoldstein, UlrichJorde
Journal: Circulation (2016)

Introduction: Despite a shortage of donor organs for adults, early adolescent (10 to 14 years) donor hearts (not used for pediatric patients) are seldom used for adults due to concerns for changes in left ventricular mass and hormonal activation during puberty. The outcome of adult transplantation using early adolescent donor hearts has not been studied. Hypothesis: Early adolescent (10 to 14 years) pediatric donor hearts have good outcomes in adult recipients. Methods: Of the 42,323 adult (≥18 yr.) heart transplant recipients in UNOS database (1994 to 2015), 35,054 met study criteria. Of these, 33,931 received hearts from adults and 1123 from early adolescent donors. Using propensity scores for ‘early adolescent pediatric donor heart use’, we assembled 944 matched pairs of adult transplants using adult vs. early adolescent pediatric donor, balanced on 30 recipient and donor characteristics. Survival, cardiac allograft vasculopathy (CAV) up to 5 years and primary graft failure (PGF) leading to death or re...
Abstract 1585: Evaluation of circulating free DNA in non-metastatic breast cancer
Authors: Jhajaira M. Araujo, Jaime Ponce, Alexis Murillo, Pamela Rebaza, Pierina Danos, Alfredo Aguilar, Ricardo Fujita, Henry L. Gomez, Joseph A. Pinto, Jose Buleje
Journal: Cancer Research (2018)

Abstract Background Circulating free DNA (cfDNA) is becoming an important tool in diagnosis and prognosis in several types of cancer. In this study we evaluated the association between cfDNA concentrations in peripheral blood with tumoral features of non-metastatic breast cancer patients. Methods cfDNA was extracted from plasma of peripheral blood of patients with non-metastatic breast cancer and healthy controls. In patients, blood samples were collected before and after surgery, while in controls samples were collected after their results of breast cancer screening. Detection of copy number of PUM1 and RNaseP genes were performed in a QuantStudio® 3D Digital PCR System and quantification was obtained with QuantStudio® 3D AnalysisSuite™ Cloud Software. Raw values were compared among the different clinicopathologic features. Results In total 26 patients and 25 controls were included. There were significant differences between controls and patients for levels counts of PUM1 and RNaseP genes (p&amp;lt;0.0001 in both cases). In patients, median concentrations before and after surgery for PUM1 were 10.6 copies/uL (range: 2.2-16.3) vs. 7.6 copies/uL (range: 1.3-12.8), respectively (P=0.04) and for RNaseP were 6.6 copies/uL (range: 0.9-20.0) vs. 5.3 copies/uL (range: 0.5-16.0), respectively (P=0.103). Hormonal tumors produced more cfDNA in terms of RNaseP at diagnosis (7.9 vs. 5.6, P=0.049). When we compared patients according to their hormonal status with controls, RNaseP was able to identified positive hormonal receptors patients (P&amp;lt;0.0001). There were no significant differences between other clinicopathologic features. There was a significant decrease after surgery of RNaseP levels in node negative tumors (P=0.049) and PUM1 levels in &amp;gt;10mm tumors (P=0.041). Conclusions Our results suggest that PUM1 is a better diagnostic biomarker for non-metastatic breast cancer because RNaseP loss sensitivity in negative hormone receptor cases. Hormonal tumors produced more circulating free DNA. RNaseP could be used to monitor node negative patients and PUM1 to patients with &amp;gt;10mm tumors. Citation Format: Jhajaira M. Araujo, Jaime Ponce, Alexis Murillo, Pamela Rebaza, Pierina Danos, Alfredo Aguilar, Ricardo Fujita, Henry L. Gomez, Joseph A. Pinto, Jose Buleje. Evaluation of circulating free DNA in non-metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1585.
Abstract 5487: Targeting glycolysis for the treatment of cancer
Authors: Jason Chesney, Aubrey Mojesky, Yoannis Imbert-Fernandez, John Trent, Sucheta Telang
Journal: Cancer Research (2018)

Abstract Tumors exhibit markedly increased glucose uptake and glycolysis and this metabolic phenotype serves to satisfy their increased requirement for energy and biosynthetic intermediates. Tumor glucose metabolism is stimulated in part by fructose-2,6-bisphosphate (F26BP), which is the product of a family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) and allosterically activates a key glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). Previous studies have found the PFKFB3 family member to be a dominant source of F26BP in cancer cells due to a high kinase activity, expression in multiple tumor types and the inhibition of tumor growth by specific PFKFB3 inhibitors including a compound, PFK158, that is currently under evaluation in a phase I trial. Recent data, however, indicate that the PFKFB4 enzyme plays a significant role in regulating glucose metabolism in neoplastic cells. We have found that PFKFB4 is highly expressed in multiple cancers, strongly induced by HIF-1α, and that its suppression markedly reduced F26BP and glycolytic flux, increased apoptosis and inhibited growth of xenograft tumors in vivo, thus providing strong rationale for the development of antineoplastic agents selectively targeting PFKFB4. Using virtual screening, we have discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity with a resultant decrease in F26BP, glycolytic flux and cancer cell growth in vitro and markedly reduces the growth of established tumors without systemic toxicity. During our studies, we unexpectedly observed that PFKFB4 expression is increased by PFKFB3 inhibition, suggesting that PFKFB4 may compensate for decreased PFKFB3 expression and activity. We examined the effects of simultaneous silencing of PFKFB4 and PFKFB3 on cancer cell lines and found that co-knockdown led to a significant decrease in cell viability and glycolysis and to a near-complete abrogation of anchorage-independent growth in vitro. We additionally examined the effect of simultaneous inhibition of PFKFB4 and PFKFB3 using 5MPN and several PFKFB3 inhibitors in vitro and found a synergistic increase in cell death. Taken together, our data indicate that targeting PFKFB4 may be a viable therapeutic option against cancer and strongly support the further development of PFKFB4 small-molecule inhibitors as well as the co-targeting of PFKFB4 and PFKFB3 as potential strategies for the treatment of cancer. Citation Format: Jason Chesney, Aubrey Mojesky, Yoannis Imbert-Fernandez, John Trent, Sucheta Telang. Targeting glycolysis for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5487.
Abstract 4430: Genistein regulates non-coding RNA HOTAIR and epithelial-to-mesenchyme transition in renal cancer cells
Authors: Mitsuho I. Sumida, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura
Journal: Cancer Research (2018)

Abstract Renal cell carcinoma (RCC) is one of the most common malignancies. Despite the development of therapeutic regimens, the prognosis of patients with RCC is poorly understood. Genistein, a naturally occurring isoflavone, has been reported to have anti-cancer effects on a variety of cancer types. While several studies have shown that genistein inhibits kidney cancer progression in various in vitro and in vivo models, the basic molecular mechanisms of genistein action have not been investigated in kidney cancer. In malignancies, long non-coding RNAs (lncRNAs) are differentially expressed in various tissues and have important functions in cell proliferation, motility and apoptosis. HOX transcript antisense RNA (HOTAIR) is a lncRNA localized in the Homeobox C gene cluster on chromosome 12. HOTAIR is necessary to target the polycomb repressive complex 2 (PRC2) in trans to the HOXD locus and can interacts with (PRC2, which enhances H3K27 trimethylation and represses the expression of tumor suppressors. HOTAIR is highly expressed in various cancers and involved in their progression and metastasis. In our study, we investigated the molecular mechanisms of genistein action through a novel pathway that represses HOTAIR. We found that HOTAIR expression is higher in renal cancer cell lines compared to normal controls. Genistein treatment was found to significantly decrease HOTAIR expression in renal carcinoma cell lines (786-O and ACHN cells). Genistein treatment also reduced expression of epithelial-to-mesenchyme transition (EMT)-related proteins, causing reduced cell migration, invasion, and increased apoptosis. We performed RNA immunoprecipitation assays, and found that genistein inhibits HOTAIR binding to PRC2. One of the other EMT markers, a tight junction protein ZO-1, is upregulated by genistein. We further investigated whether genistein represses PRC2 recruitment to the ZO-1 promoter by inhibiting binding of HOTAIR to PRC2. In this study, we revealed detailed mechanism of antitumor action of genistein. These insights indicate that genistein is a potent therapeutic agent not only for renal cancer but also for a broad spectrum of cancers. Citation Format: Mitsuho I. Sumida, Yuichiro Tanaka, Rajvir Dahiya, Soichiro Yamamura. Genistein regulates non-coding RNA HOTAIR and epithelial-to-mesenchyme transition in renal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4430.
Abstract 784: NCI CPTAC phase III, proteogenomic analysis of 10 cancers
Authors: Mathangi Thiagarajan
Journal: Cancer Research (2018)

Abstract The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) is an international effort to accelerate the understanding of the molecular basis of cancer through the application of large-scale proteomic and genomic analysis, or proteogenomics. Leidos Biomedical Research, a prime contractor to NCI, provides a robust infrastructure for supporting the collection and sequencing of high-quality biospecimens and data, in addition to project and subcontract management for this program. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. CPTAC phase III began late 2016 to collect and analyze 200 cases of each of ten additional cancers. The cancers include sarcoma, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, uterine corpus endometrial carcinoma, clear cell renal cell carcinoma, glioblastoma multiforme, and acute myeloid leukemia. The program completed the discovery phase collection of 100 cases for 3 tumor types in the first year. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to sequencing centers and tissues to proteomics groups. Data are combined and analyzed by proteogenomic data analysis and translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons. Proteomic and proteogenomic data are made available through the Data Coordinating Center. Imaging data are made available through NCI imaging archive. We report here on progress in collection of tissues and clinical data, the preliminary analysis trends and the integration of biorepository, proteomics and genomics and analysis centers. Citation Format: Mathangi Thiagarajan. NCI CPTAC phase III, proteogenomic analysis of 10 cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 784.
Abstract 2847: Investigation of the combinatorial treatment strategy for BRAFmutant anaplastic thyroid cancer based on real time monitoring technology
Authors: Hyung Kwon Byeon, Minhee Ku, Ji Hye Choi, Hyunjung Kee, Ji-Hoon Kim, Yoon Woo Koh, Jaemoon Yang
Journal: Cancer Research (2018)

Abstract Purpose Previously, we have identified that c-Met-mediated reactivation of PI3K/AKT pathway contributes to acquired resistance to BRAF inhibitor in BRAF mutant (BRAFm) anaplastic thyroid cancer (ATC). So dual inhibition of BRAF and c-Met led to sustained treatment response. However, previous RTK array result in 8505C cells following PLX4032 treatment revealed increased expression of Src together with c-Met. Therefore further in-depth investigation is required to elucidate the optimal combinatorial strategy to maximize the treatment effects in BRAFm ATC. Using non-invasive, real-time monitoring in vitro and in vivo technologies, the best treatment strategy was investigated with consideration of not only the specific treatment regimens but also the mode of combinatorial treatment. Methods Real-time cell analysis (RTCA), a cell-based label-free technology using electronic impedance sensors was adopted as a strategy for real-time screening of cellular response to drugs. Live wound healing assays with supporting live cell microscopy and confocal microscopy were conducted for in vitro analyses and both ectopic xenograft and metastatic mouse models were utilized for in vivo analyses. Tumor characteristics were evaluated using 9.4T MR diffusion weighted imagings. Results Dual inhibition of BRAF and c-Met was not fully effective in overcoming BRAF inhibitor resistance in BRAFm ATC. Src-mediated signal has a greater contribution than c-Met-mediated signaling in conferring BRAF inhibitor resistance. Inhibition of Src exerted a more potent effect than c-Met inhibition. Simultaneous drug treatment was more effective than sequential therapy. Combinatorial treatment of BRAF inhibitor (PLX4032) and Src inhibitor (dasatinib) presented the maximal therapeutic effect against BRAFm ATC. Conclusions Real-time/non-invasive monitoring assays sensitively provides more accurate information regarding drug response. Citation Format: Hyung Kwon Byeon, Minhee Ku, Ji Hye Choi, Hyunjung Kee, Ji-Hoon Kim, Yoon Woo Koh, Jaemoon Yang. Investigation of the combinatorial treatment strategy for BRAFmutant anaplastic thyroid cancer based on real time monitoring technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2847.