tbuckley/cabot-search huggingface dataset:
Abstract 4199: Resveratrol induced <i>REG III</i> and inhibited head and neck cancer progression
Authors: Ichiro Ota, Shinji Mikami, Takashi Masui, Takahiro Kimura, Hirokazu Uemura, Hideyuki Okamoto, Shin Takasawa, Takashi Kitahara, Ryogo Shobatake
Journal: Cancer Research (2018)

Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common malignancies in the world and known for clinical progression and poor prognosis. Despite the recent progress of the treatment for improving locoregional control in HNSCC patients, that for recurrence and metastatic control remains insufficient, indicating that there is a continued need for improved treatment strategies. Therefore, the key molecules that enhance chemo- and radio-sensitivity in HNSCC and identification of reliable biomarkers for predicting the recurrence and metastasis would be desirable to improve the prognosis of HNSCC. The human regenerating gene (REG) expression has been reported to be associated with progression of various cancers. Recently, we have reported that REG III expression is associated with an improved survival rate for HNSCC patients as a reliable biomarker. Herein, we investigated the inducer for REG III expression in HNSCC cells and found that resveratrol significantly increased the REG III promoter activity and REG III mRNA. In addition, we demonstrated that the effects of resveratrol on cancer cell progression in HNSCC in vitro and in vivo. To reveal the effects of resveratrol on HNSCC cell proliferation, cell proliferation was measured by using WST-8 assay. Resveratrol significantly inhibited cell growth in FaDu and HSC-4 HNSCC cells. Secondly, to check the effects of resveratrol on chemo- and radio-sensitivity in HNSCC cells, HNSCC cells were expose to cisplatin and radiation, respectively. Resveratrol significantly increased the sensitivity of cisplatin and radiation in HNSCC cells. We also examined the effects of resveratrol on cancer invasion using 24-well Matrigel-coated Transwells. Resveratrol significantly attenuated the cancer invasion of HNSCC cells. Moreover, to assess resveratrol-induced chemo-sensitivity in vivo, we established a xenograft model of HNSCC in BALB/c nude mice. The tumor volumes in the mice receiving combined administration of resveratrol and cisplatin were significantly lower than those of resveratrol or cisplatin alone. These results strongly suggest that resveratrol can inhibit head and neck cancer progression through the REG III expression pathway and can be a potential sensitizer for anticancer therapy for patients with HNSCC. Citation Format: Ichiro Ota, Shinji Mikami, Takashi Masui, Takahiro Kimura, Hirokazu Uemura, Hideyuki Okamoto, Shin Takasawa, Takashi Kitahara, Ryogo Shobatake. Resveratrol induced REG III and inhibited head and neck cancer progression [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 4199.
Differential Pacing for Distinguishing Block From Persistent Conduction Through an Ablation Line
Authors: DipenShah, MichelHaïssaguerre, AtsushiTakahashi, PierreJaïs, MélèzeHocini, JacquesClémenty
Journal: Circulation (2000)

Background—Because complete linear conduction block is necessary to minimize the recurrence of reentrant tachycardias such as typical atrial flutter, we investigated a simple technique to recognize a persistent gap or complete linear block. Methods and Results—We prospectively evaluated cavotricuspid isthmus conduction in 50 patients (age 63±8 years, 43 men) after radiofrequency ablation. The distal and proximal bipoles of a quadripolar catheter placed close to the ablation line were successively stimulated during recording from the ablation line. We hypothesized that because the initial and terminal components of local potentials reflected activation at the ipsilateral and contralateral borders of the ablation lesion, a change to a more proximal pacing site without moving the catheter would prolong the stimulus to the initial component timing, whereas the response of the terminal component would depend on the presence of block or persistent conduction. A shortening or no change in timing of the terminal ...
Radionuclide imaging of VEGFR2 in glioma vasculature using biparatopic affibody conjugate: proof-of-principle in a murine model
Authors: Bogdan Mitran, Rezan Güler, Francis P. Roche, Elin Lindström, Ram Kumar Selvaraju, Filippa Fleetwood, Sara S. Rinne, Lena Claesson-Welsh, Vladimir Tolmachev, Stefan Ståhl, Anna Orlova, John Löfblom
Journal: Theranostics (2018)

Vascular endothelial growth factor receptor-2 (VEGFR2) is a key mediator of angiogenesis and therefore a promising therapeutic target in malignancies including glioblastoma multiforme (GBM).Molecular imaging of VEGFR2 expression may enable patient stratification for antiangiogenic therapy.The goal of the current study was to evaluate the capacity of the novel anti-VEGFR2 biparatopic affibody conjugate (ZVEGFR2-Bp2) for in vivo visualization of VEGFR2 expression in GBM.Methods: ZVEGFR2-Bp2 coupled to a NODAGA chelator was generated and radiolabeled with indium-111.The VEGFR2-expressing murine endothelial cell line MS1 was used to evaluate in vitro binding specificity and affinity, cellular processing and targeting specificity in mice.Further tumor targeting was studied in vivo in GL261 glioblastoma orthotopic tumors.Experimental imaging was performed.Results: [ 111 In]In-NODAGA-ZVEGFR2-Bp2 bound specifically to VEGFR2 (KD=33±18 pM).VEGFR2-mediated accumulation was observed in liver, spleen and lungs.The tumor-to-organ ratios 2 h post injection for mice bearing MS1 tumors were approximately 11 for blood, 15 for muscles and 78 for brain.Intracranial GL261 glioblastoma was visualized using SPECT/CT.The activity uptake in tumors was significantly higher than in normal brain tissue.The tumor-to-cerebellum ratios after injection of 4 µg [ 111 In]In-NODAGA-ZVEGFR2-Bp2 were significantly higher than the ratios observed for the 40 µg injected dose and for the non-VEGFR2 binding size-matched conjugate, demonstrating target specificity.Microautoradiography of cryosectioned CNS tissue was in good agreement with the SPECT/CT images. Conclusion:The anti-VEGFR2 affibody conjugate [ 111 In]In-NODAGA-ZVEGFR2-Bp2 specifically targeted VEGFR2 in vivo and visualized its expression in a murine GBM orthotopic model.Tumor-to-blood ratios for [ 111 In]In-NODAGA-ZVEGFR2-Bp2 were higher compared to other VEGFR2 imaging probes.[ 111 In]In-NODAGA-ZVEGFR2-Bp2 appears to be a promising probe for in vivo noninvasive visualization of tumor angiogenesis in glioblastoma.
Lysophosphatidylcholine Increases Expression of Heparin-Binding Epidermal Growth Factor–Like Growth Factor in Human T Lymphocytes
Authors: EiichiroNishi, NoriakiKume, HiroshiOchi, HideakiMoriwaki, YoshioWakatsuki, ShigekiHigashiyama, NaoyukiTaniguchi, ToruKita
Journal: Circulation Research (1997)

Abstract Atherosclerotic lesions contain substantial numbers of activated T lymphocytes in addition to monocytes/macrophages. T cell–derived cytokines and growth factors may play a role in atherogenesis; however, stimuli responsible for T-cell activation in atherogenesis have not been fully elucidated. In this study, we provide evidence that lysophosphatidylcholine (lyso-PC), a polar phospholipid component increased in atherogenic lipoproteins and atherosclerotic lesions, can upregulate gene expression and secretion of heparin-binding epidermal growth factor–like growth factor (HB-EGF) in cultured T lymphocytes isolated from human peripheral blood. Effects of lyso-PC on T lymphocytes appear to be selective and specific, since lyso-PC also increases interleukin (IL)-2 receptor expression but does not affect mRNA levels for IL-2 or IL-4. Lyso-PC–induced upregulation of HB-EGF and IL-2 receptor mRNA in peripheral T cells is mostly dependent on exogenous IL-2 in conditioned medium. The effect of lyso-PC on HB...
Angiotensinogen Gene–Activating Elements Regulate Blood Pressure in the Brain
Authors: TadahikoNishii, AtsushiMoriguchi, RyuichiMorishita, KazuoYamada, ShigefumiNakamura, NaruyaTomita, YasufumiKaneda, AkiyoshiFukamizu, HiroshiMikami, JitsuoHigaki, ToshioOgihara
Journal: Circulation Research (1999)

Abstract—Although the angiotensinogen gene is a possible candidate as a determinant of hypertension, the molecular mechanisms of tissue angiotensinogen gene regulation have yet to be clarified. We identified essential transcription regulators of angiotensinogen production in the central nervous system using synthetic double-stranded oligodeoxynucleotides (ODNs) as “decoy” cis elements to block the binding of nuclear factors to promoter regions of the targeted gene. Using a gel mobility shift assay, angiotensinogen gene–activating element (AGE) 2 binding protein was detected in the brain nuclear extracts of both spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs). Importantly, the binding activity of AGE 2 and angiotensinogen mRNA level were significantly higher in the brain of SHRs than in that of WKYs. Using the decoy approach, we demonstrated a significant decrease in the blood pressure of SHRs by transfection of AGE 2 decoy, but not mismatched, ODNs into the lateral cerebro...
Abstract 1906: <i>PFKFB4</i>, much more than just a glycolytic gene
Authors: Emma L. Phillips, Frederic Bethke, Jörg Balss, Stefan Pusch, Stefan Christen, Martina Schnölzer, Antje Habel, David Capper, Andreas Von Deimling, Sarah-Maria Fendt, Peter Lichter, Violaine Goidts
Journal: Cancer Research (2018)

Abstract Glioblastoma is one of the most aggressive primary brain tumors in adults, with a dismal median overall survival of only 14 months after diagnosis. Glioblastoma stem-like cells (GSCs) are particularly resistant to current therapies, capable of self-renewal and tumour initiation and are hence thought to be major contributors to patient relapse. A kinome and phosphatome wide screen revealed glycolysis gene 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) as an important candidate gene for GSC survival. Notably, silencing PFKFB4 in an orthotopic xenograft mouse model of glioblastoma completely rid the mice of the tumor. Here we show a brand new function of PFKFB4, independent of its role in glycolysis - namely in the regulation of HIF1α, which is upregulated in GSCs. Gene expression profiling revealed a downregulation in HIF1α target genes in PFKFB4-silenced GSCs, and HIF1α protein levels are also dramatically reduced upon silencing. Mass spectrometric analysis of immunoprecipitated PFKFB4 protein revealed a novel interaction partner, F-box only protein 28 (FBXO28), an E3 ubiqutin ligase. Co-immunoprecipation assays show that FBXO28 forms an SCF multi-protein ubiquitin ligase complex with CUL1 and SKP1. Ubiquitylation studies of HIF1α show that PFKFB4 stabilizes this crucial protein in GSCs by preventing its targeting by FBXO28 for proteasomal degradation. These new findings, coupled with its cancer specific expression in a variety of tumor entities, makes PFKFB4 a compelling target. Citation Format: Emma L. Phillips, Frederic Bethke, Jörg Balss, Stefan Pusch, Stefan Christen, Martina Schnölzer, Antje Habel, David Capper, Andreas Von Deimling, Sarah-Maria Fendt, Peter Lichter, Violaine Goidts. PFKFB4, much more than just a glycolytic gene [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 1906.
Abstract 14026: Inter-ethnic Differences in Bicuspid Aortic Valve Morphology, Valvular Dysfunction and Aortopathy : Result From a Large Multi-Center International Registry
Authors: William K Kong, Mara Vollema, Medelien Regeer, Kian Keong Poh, James Yip, Philippe van Rosendael, Tiong Cheng Yeo, Lieng Hsi Ling, Vasilis Kamperidis, Michael Liang, Edgar Tay, Enno. T van der Velde, Bart Mertens, Nina A Marsan, Victoria Delgado, Jeroen J Bax
Journal: Circulation (2016)

Introduction: Bicuspid aortic valve (BAV) is the most common congenital valve defect. However, the inter-ethnic differences in morphology, valvular dysfunction and aortopathy data are lacking in th...
Abstract 2397: Intracellular cholesterol regulates the DNA damage response in inflammatory breast cancer
Authors: Shane R. Stecklein, Adam R. Wolfe, Bisrat G. Debeb, Richard A. Larson, Wendy A. Woodward
Journal: Cancer Research (2018)

Abstract Purpose: Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer, and patients with IBC remain at high risk of locoregional recurrence after radiotherapy. We previously demonstrated that depleting intracellular cholesterol induces radiosensitivity in IBC cells in vitro, and that IBC patients with high levels of high-density lipoprotein (HDL) and those taking a statin, which inhibits de novo cholesterol biosynthesis, have improved locoregional control after radiotherapy. These results suggest that targeting cholesterol metabolism may improve the radiotherapeutic management of IBC. Here, we aimed to understand the molecular mechanism(s) linking cholesterol metabolism and radiation-induced DNA damage and DNA repair and to evaluate statin pharmacotherapy as a DNA repair inhibitor and radiotherapeutic adjunct in an in vivo pre-clinical model of IBC. Methods: KPL4, SUM149, SUM190, and IBC3 IBC cell lines were used to examine the effect(s) of simvastatin and human serum lipoproteins on radiation-induced DNA damage induction, DNA damage signaling, DNA damage-associated G1, intra-S, and G2/M cell cycle checkpoint activation, and DNA double strand break (DSB) repair by homologous recombination (HR) and non-homologous end joining (NHEJ). Results: We have generated multiple IBC cells lines with an integrated Traffic Light Reporter (TLR) that is capable of measuring HR and NHEJ, and demonstrate that depletion of intracellular cholesterol abrogates HR-mediated repair of DNA DSBs. We also show that intracellular cholesterol has pleiotropic effects on cell cycle distribution and DNA damage-associated cell cycle checkpoints. We also report a novel polycistronic dual bioluminescence reporter system that can robustly visualize and quantitate DNA DSB induction and repair in vitro and in vivo. Conclusions: Cholesterol is an important determinant of intrinsic radiosensitivity in IBC, and appears to regulate repair of radiation-induced DNA DSBs. Targeting cholesterol metabolism is a potential strategy to overcome IBC radioresistance and improve the prognosis for this aggressive disease. Citation Format: Shane R. Stecklein, Adam R. Wolfe, Bisrat G. Debeb, Richard A. Larson, Wendy A. Woodward. Intracellular cholesterol regulates the DNA damage response in inflammatory 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 2397.
Dual purpose hafnium oxide nanoparticles offer imaging Streptococcus mutans dental biofilm and fight it In vivo via a drug free approach
Authors: Fatemeh Ostadhossein, Santosh K. Misra, Indu Tripathi, Valeriya Kravchuk, Gururaja Vulugundam, Denae LoBato, Laura E. Selmic, Dipanjan Pan
Journal: Biomaterials (2018)
Abstract 2801: Novel selenodiazoles as antitumor and radical scavenging agents
Authors: Ana Carolina Ruberte, Daniel Plano, Ignacio Encio, Arun K. Sharma, Carmen Sanmartin
Journal: Cancer Research (2018)

Abstract Heterocyclic compounds with selenium atom in endo position, such as ebselen (EBS), have achieved very promising activity against cancer and hold an excellent pharmacological profile. In fact, EBS is currently under Phase II clinical trial for the evaluation of its therapeutic safety and efficacy. The purpose of this study was to make structural modifications over this scaffold to improve its anticancer and antioxidant characteristics. Twenty-eight novel benzo[c][1,2,5]selenodiazole-5-carboxamide derivatives were designed and synthesized. Cytotoxicity of these structures, using the MTT assay, was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). The selectivity of all the compounds was further examined in two non-malignant cell lines derived from breast (184B5) and lung (BEAS-2B). For MCF-7 cells, the apoptotic status and cell cycle analysis of the cells were based on the TUNEL technique. Likewise, their radical scavenging activity was determined using the DPPH assay. Interestingly, three compounds exhibited higher cytotoxic activity than EBS in solid tumors, along with higher selectivity indexes. The cytotoxic activity of lead compound 8 was remarkable in MCF-7 cells. The antioxidant capacity of four compounds was greater than EBS. The toxicity of derivative 8 in the non-tumoral cell line 184B5 was low (lethal dose (LD50) &amp;gt; 100 µM) and it exhibited promising antiproliferative values in MCF-7 cells with a growth inhibition of 50% (GI50) of 3.7 µM. The radical scavenging capacity of four compounds was greater than EBS. Given the low toxicity and moderate antioxidant activity, these compounds can serve as an excellent scaffolds to achieve new and potent antioxidant compounds useful for several diseases such as cancer, neurodegenerative and heart diseases. Citation Format: Ana Carolina Ruberte, Daniel Plano, Ignacio Encio, Arun K. Sharma, Carmen Sanmartin. Novel selenodiazoles as antitumor and radical scavenging agents [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 2801.
Loss of Nuclear Localized Parathyroid Hormone-Related Protein in Primary Breast Cancer Predicts Poor Clinical Outcome and Correlates with Suppressed Stat5 Signaling
Authors: Thai H. Tran, Fransiscus E. Utama, Takahiro Sato, Amy R. Peck, John F. Langenheim, Sameer S. Udhane, Yunguang Sun, Chengbao Liu, Melanie A. Girondo, Albert J. Kovatich, Jeffrey A. Hooke, Craig D. Shriver, Hai Hu, Juan P. Palazzo, Marluce Bibbo, Paul W. Auer, Michael J. Flister, Terry Hyslop, Edith P. Mitchell, Inna Chervoneva, Hallgeir Rui
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Parathyroid hormone-related protein (PTHrP) is required for normal mammary gland development and biology. A PTHLH gene polymorphism is associated with breast cancer risk, and PTHrP promotes growth of osteolytic breast cancer bone metastases. Accordingly, current dogma holds that PTHrP is upregulated in malignant primary breast tumors, but solid evidence for this assumption is missing. Experimental Design: We used quantitative IHC to measure PTHrP in normal and malignant breast epithelia, and correlated PTHrP levels in primary breast cancer with clinical outcome. Results: PTHrP levels were markedly downregulated in malignant compared with normal breast epithelia. Moreover, low levels of nuclear localized PTHrP in cancer cells correlated with unfavorable clinical outcome in a test and a validation cohort of breast cancer treated at different institutions totaling nearly 800 cases. PTHrP mRNA levels in tumors of a third cohort of 737 patients corroborated this association, also after multivariable adjustment for standard clinicopathologic parameters. Breast cancer PTHrP levels correlated strongly with transcription factors Stat5a/b, which are established markers of favorable prognosis and key mediators of prolactin signaling. Prolactin stimulated PTHrP transcript and protein in breast cancer cell lines in vitro and in vivo, effects mediated by Stat5 through the P2 gene promoter, producing transcript AT6 encoding the PTHrP 1-173 isoform. Low levels of AT6, but not two alternative transcripts, correlated with poor clinical outcome. Conclusions: This study overturns the prevailing view that PTHrP is upregulated in primary breast cancers and identifies a direct prolactin–Stat5–PTHrP axis that is progressively lost in more aggressive tumors.
Abstract 3375: The chromosomal instability in tumorigenesis of esophageal squamous cell carcinoma
Authors: Ting Yan, Xiaolong Cheng, Yongping Cui
Journal: Cancer Research (2018)

Abstract Chromosomal instability (CIN) is the leading cause of the cell genome instability and is a common trait of more than 70% of human cancers, therefore is implicated as an initiator of tumorigenesis. More importantly, CIN may facilitate the adaptation of tumors to environmental or stromal stress and is implicated in determining tumor progression and associated with poor outcome, tumor relapse, and multi-drug resistance across a range of cancer types. The latest studies suggest that cancer is the result of micro-evolution altermate with macro-evolution. That means the cells get mutations through micro-evolution and expansion by the mutational accumulation; the cells begin to undergo macro-evolution instead of micro-evolution when encounter tumorigenic factors, and CIN will be the main driver for tumor evolution. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. We integrated 31 whole genomic sequencing data of ESCC samples from China to investigate underlying evolutionary characteristics in ESCC. We combined copy number profiles of 1660 cancer specimens from 5 types of gestrointestinal tumors. Different from colorectal carcinoma, liver hepatocellular carcinoma, pancreatic adenocarcinoma and stomach adenocarcinoma, ESCC possesses largely copy number alterations, and frequent copy-number changes were not clustered in specific chromosome. In our cohort, we found whole genome doubling (WGD) that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome. Moreover, loss of heterozygosity events was more likely to occur in chromosomes harboring tumor suppressor genes in ESCC. The 40% of neutral loss of heterozygosity events was not a result of genome doubling suggesting an alternative mechanism for neutral loss of heterozygosity formation. Importantly, deconstruction of copy number alterations extending to telomere revealed that telomere-bounded copy number alterations play a critical role for amplification/deletion of oncogenes/suppressor genes. For well-known genes SOX2, PIK3CA and TERT, almost all of their amplifications were telomere bounded, which was further confirmed in a Japanese ESCC cohort. Furthermore, we provide evidence that karyotype evolution was mostly punctuated in ESCC. Collectively, our data reveal the potential biological role of whole genome doubling, neutral loss of heterozygosity and telomere-bounded copy number alterations, and highlight macro-evolution in ESCC tumorigenesis. Citation Format: Ting Yan, Xiaolong Cheng, Yongping Cui. The chromosomal instability in tumorigenesis of esophageal squamous cell carcinoma [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 3375.