bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4798: The Ashitaba (Angelica keiskei) chalcones 4-hydroxyderricin and xanthoangelol suppress melanomagenesis by targeting BRAF and PI3-K
Authors: Zhang Tianshun , Wang Qiushi , Ashida Hitoshi , Bode Ann , Dong Zigang 
Published: August 2019

Abstract
Malignant melanoma is an aggressive tumor of the skin and still lacks effective preventive and therapeutic approaches. In melanoma, both the BRAF/MEK/ERK and PI3-K/AKT signaling pathways are constitutively activated though multiple mechanisms, which result in cell cycle progression and prevention of apoptosis. Therefore, the development of novel strategies for targeting BRAF and PI3-K are of utmost importance. In the current study, we found that the Ashitaba (Angelica keiskei) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma carcinogenesis by directly targeting both BRAFV600E and PI3-K, which blocked the activation of downstream signaling. This led to the induction of G1 phase cell cycle arrest and apoptosis in melanoma cells. Importantly, 4HD and XAG dramatically attenuated tumor incidence and volume in the BRAF-activated Pten-deficient melanoma mouse model. Our findings suggest that 4HD and XAG are promising chemopreventive or potential therapeutic agents against melanomagenesis that act by targeting both BRAF and PI3-K, providing hope for rapid clinical translation.
Citation Format: Tianshun Zhang, Qiushi Wang, Hitoshi Ashida, Ann Bode, Zigang Dong. The Ashitaba (Angelica keiskei) chalcones 4-hydroxyderricin and xanthoangelol suppress melanomagenesis by targeting BRAF and PI3-K [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4798.
Abstract 4802: In vitro characterization of TP-2846: a novel tetracycline antileukemia agent
Authors: Fyfe Corey , Newman Joseph , Bhargava Ajay , Ballesteros Juan , Robles Alicia , Sun Cuixiang , Xiao Xiao-Yi , Dumas Jacques 
Published: August 2019

Abstract
Recently published studies suggest two hypotheses for the mechanism of action (MOA) of tetracyclines’ anticancer activities: a) disruption of mitochondrial translation (Škrtić, Cancer Cell (2011) 20(5): 10.015); b) regulation of the miRNA-199b-5p-HES1-AKT pathway (Yang, Mol Cancer Ther (2016) 15(3): 1535-7163.MCT-15-0709). Upon treatment with TP-2846, suppressed levels of cytochrome oxidase-1 (COX-1) levels were demonstrated in Western blots. The COX-1 mRNA accumulated approximately 1,000-fold over background levels after 48 h incubation. Furthermore, TP-2846 displayed sub-µM inhibitory activities to mitochondrial translation (IC50 = 0.71 µM) and ribosomal translation both in E. coli and in eukaryotes (IC50 = 0.56 µM and 3.75 µM, respectively).
In addition, TP-2846 led to accumulation of the micro RNA miR-199b in MV4-11 and HL-60 cells after 24 h incubation. TP-2846 had minimal IC50 shift (Resistance Factor (RF) = 1.53) against K-562/ADR, a leukemia cell line overexpressing P-glycoprotein (Pgp), while daunorubicin displayed an RF value of 3.67 in the same assay. TP-2846 was also studied ex vivo using bone marrow samples from 15 AML patients, including those resistant to AraC, and displayed potent activity in all samples (EC50 = 150-250 nM), while anthracyclines had similar activity (EC50 = 100-600 nM) and AraC was 10x less potent (EC50 = 2.3 µM) in the same ex vivo assay.
In summary, TP-2846 exhibits both anticancer MOAs described in the literature for tetracyclines, retains antiproliferation activity in resistant leukemia cell lines, and demonstrates promising ex vivo activity in bone marrow samples from AML patients. This data indicates that further investigations in vitro and in vivo are warranted (see accompanying abstract “In vivo activities of TP-2846: a novel tetracycline antileukemia agent”).
Citation Format: Corey Fyfe, Joseph Newman, Ajay Bhargava, Juan Ballesteros, Alicia Robles, Cuixiang Sun, Xiao-Yi Xiao, Jacques Dumas. In vitro characterization of TP-2846: a novel tetracycline antileukemia agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4802.
Abstract 4806: Development of a novel antitumor agent NCT compound for the treatment of non-small cell lung cancer
Authors: Hyun Seung Yeob , Le Huong Thuy , Yong Young-Sik , Min Hye-Young , Lee Jeewoo , Lee Ho-Young 
Published: August 2019

Abstract
Despite the development of advanced therapeutic regimens such as molecular targeted therapy and immunotherapy, the 5-year survival of patients with lung cancer is still less than 20%, suggesting the need to develop additional treatment strategies. Here we show the efficacy and biological mechanism of a novel antitumor agent, NCT compound. NCT compound exhibited significant inhibitory effects on the viability and colony formation of non-small cell lung cancer (NSCLC) cells and those carrying resistance to chemotherapy by inducing apoptosis. NCT compound markedly suppressed the migration of NSCLC cells. Consistently, NCT compound significantly suppressed tumor growth in a xenograft model. NCT compound showed minimal effects on the viability of normal cells and no overt toxic effects in mice, suggesting minimal toxicity of NCT compound. Further mechanistic studies revealed that NCT compound downregulated the activation of signaling pathway associated with cell proliferation and survival and the expression of epithelial-mesenchymal transition (EMT)-related markers. These results suggest the potential of NCT compound as an antitumor agent.
Citation Format: Seung Yeob Hyun, Huong Thuy Le, Young-Sik Yong, Hye-Young Min, Jeewoo Lee, Ho-Young Lee. Development of a novel antitumor agent NCT compound for the treatment of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4806.
Abstract 4810: Olive oil-derived (-)-oleocanthal for prevention of breast cancer recurrence
Authors: Siddique Abu Bakar , Ayoub Nehad M. , Sayed Khalid A. El 
Published: August 2019

Abstract
Despite progress in BC therapy and improved survival rates, several breast cancer (BC) patients have poor recurrence-free rates. More than three million BC survivors are currently at the risk of disease recurrence without feasible preventive options. Surgical excision of early-stage confined breast tumors commonly used to minimize subsequent metastasis. Neoadjuvant and adjuvant therapeutic agents usually cannot prevent BC recurrence. There is a dire need to discover novel recurrence and metastasis inhibitory entities because clinical trials on early-stage cancer patients survival and metastases/recurrence reduction endpoint is not financially feasible and need large patients number. Mediterranean populations have less colon and breast cancers incidence due to their dietary consumption of significant amounts of phenolics-rich extra-virgin olive oil (EVOO). (-)-Oleocanthal (OC) is the most bioactive EVOO phenolic with diverse activities and exceptional in vivo potency. Validated molecular targets of OC in BC include the inhibition of the activation of the RTKs c-Met and HER2 and modulation of estrogen receptors (ER). Met/HER2/ER amplification is implicated in activation of quiescent breast tumor cells, repopulation, subsequent recurrence and relapse. This study reports the potent ability of four-weeks oral 10 mg/kg OC treatments to inhibit more than 90% of local and regional triple negative and hormone-dependent breast tumors recurrence after the surgical excision of orthotopically xenografted primary breast tumors. Oral OC treatments also potently inhibited recurrence after surgical excision of breast tumors subjected to neoadjuvant therapies with either lapatinib (50 mg/kg, 5X/week, 4 weeks) or paclitaxel (4.5 mg/kg, ip, 3X/week for 6 weeks) in athymic orthotopic nude mice models. This was associated with significant reductions of p-c-Met and p-HER2 levels in treated animal tumors by Western blotting. OC-treated mice sera completely lacked the BC recurrence marker CA 15-3, unlike vehicle treated controls which showed significantly high CA 15-3 levels. OC treatment did not show any observable toxicity and did not affect animals body weight over the experiment course. OC is a novel breast cancer recurrence inhibitory dietary supplement lead with excellent clinical applications potential.
Note: This abstract was not presented at the meeting.
Citation Format: Abu Bakar Siddique, Nehad M. Ayoub, Khalid A. El Sayed. Olive oil-derived (-)-oleocanthal for prevention of breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4810.
Abstract 4840: Characterization of URST1 as a biomarker and therapeutic target for precision medicine of lung cancer
Authors: Takano Atsushi , Miyagi Yohei , Daigo Yataro 
Published: August 2019

Abstract
This study aims to identify novel biomarkers and therapeutic targets for lung cancer. We initially screened genes that overexpressed in the majority of lung cancers by using our original gene expression profile database. During this process, we identified up-regulated in solid tumor 1 (URST1) as a candidate. Immunohistochemical staining showed that URST1 was expressed in 231 (64.5%) of 358 non-small cell lung cancer (NSCLC) that had undergone curative surgery. Strong URST1 expression was associated with poor prognosis for NSCLC patients (P = 0.0003 by log-rank test). In addition, multivariate analysis showed that strong URST1 expression was an independent prognostic factor for NSCLC patients. Reduction of URST1 expression by siRNA or treatment with selective URST1 inhibitor significantly suppressed cancer cell growth partly through cell cycle arrest at G2/M phase and mitotic cell death as detected by flow cytometric analysis and live cell imaging. Our findings suggest that URST1 could be a potential biomarker and therapeutic target for developing precision medicine of lung cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Atsushi Takano, Yohei Miyagi, Yataro Daigo. Characterization of URST1 as a biomarker and therapeutic target for precision medicine of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4840.
Abstract 4856: Suppression of PRKCI gene-amplified ovarian cancer using aptamer-delivered siRNA
Authors: Rehmani Hina 
Published: August 2019

Abstract
Ranked fifth in cancer death among women, ovarian cancer cure rates have remained at 30% over the past two decades. Treatment options have steadily followed the same methodology, surgery and then first-line chemotherapy. With a 70% relapse rate within the first two years of diagnosis and limited secondary options, acquiring more targeted treatments is imperative. Copy number aberrations, more than mutations, are commonly found in high grade serous ovarian cancer. Copy number gains of the Protein Kinase C iota (PRKCI) gene are found in over 33% of ovarian cancer patients. According to the TCGA database, patients with PRKCI gene amplification have a significantly poor overall survival than those that do not. With this information and the fact that it is a previously identified oncogene in ovarian cancer, Protein Kinase C iota (PKCi) serves as an excellent target. Unfortunately, the Protein Kinase C iota isoform shares an overall homology of 72% with the Protein Kinase C zeta isoform which makes selective targeting of the iota form a challenge. Previous publications have used gold-based compounds to block atypical PKC family members from interactions that are crucial for apical-basal polarity. We found, however, that these compounds exhibit no specific selectivity for PRKCI gene amplified ovarian cancer cell lines.To specifically target PKCi, we have created an RNA-based aptamer that contains a siRNA sequence against the PRKCI mRNA and EpCAM moieties on either end. The aptamer efficiently becomes internalized after binding to the cell surface EpCAM via clathrin-dependent endocytosis. Once inside, the aptamer is processed by Dicer to release the two unique siRNA duplex intermediates. The guide strand of the siRNA loads into the RNA-induced silencing complex (RISC) complex and Argonaute (Ago) protein family members mediate PRKCI mRNA silencing.We hypothesize that PRKCI gene amplification status offers a unique opportunity to stratify patients into different risk categories and RNA-aptamer targeting of PRKCI can provide therapeutic benefits, by impairing ovarian cancer cell proliferation and tumorigenesis. We expect this approach to provide potent and selective anti-tumor and anti-metastasis activity compared to targeting using other pharmaceutical options.
Citation Format: Hina Rehmani. Suppression of PRKCI gene-amplified ovarian cancer using aptamer-delivered siRNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4856.
Abstract 488: Direct real-time visualization and quantification of T cell receptor dynamics
Authors: Rosenberg Jillian N. , Cao Guoshuai , Borja-Prieto Fernanda , He Yanran , Schreiber Hans , Huang Jun 
Published: August 2019

Abstract
The mechanism by which a T cell utilizes its T-cell receptors (TCRs) to recognize foreign peptide major histocompatibility complexes (pMHCs) has not yet been fully deciphered. Much contention still exists surrounding TCR nanostructures before, during, and after synapse formation. Accurate measurements of single TCR location, diffusion/trafficking, clustering, and signaling at the live T-cell membrane have been hindered by the microscopy techniques available. Recently developed Lattice Light-Sheet Microscopy uses a structured light sheet to excite fluorescence in successive planes of a living T cell such that it can record 4D (x, y, z directions and time) images with exceptionally high temporal resolution (10ms/frame, ~1s/volume), finally allowing for precise single molecule tracking. Here we show that TCRs pre-exist in small microclusters prior to synapse formation in both naïve and stimulated resting CD4+ T cells. These clusters are very fast-moving, explaining the previous difficulties of tracking TCR motion and revealing a fast responding mechanism for antigen recognition. Upon encountering antigens, these smaller TCR nanoclusters traffic globally and quickly to the cell interface, aggregate into larger microclusters, and form the immunological synapse. Finally, we compare and contrast the receptor dynamics of CAR-T cells with those of naturally occurring T cell receptors. These findings precisely quantify TCR and CAR dynamics three-dimensionally, suggesting new mechanistic details of the speed and accuracy of TCR signaling and providing new information upon which to base future immunotherapies.
Citation Format: Jillian N. Rosenberg, Guoshuai Cao, Fernanda Borja-Prieto, Yanran He, Hans Schreiber, Jun Huang. Direct real-time visualization and quantification of T cell receptor dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 488.
Abstract 4888: Nuclear localization of antizyme inhibitor may be a marker for aggressiveness of prostate cancer
Authors: Ghalali Aram , Rice James M. , Wang Liangzhe , Wu Chin Lee , Rogers Michael S. , Zetter Bruce 
Published: August 2019

Abstract
Antizyme suppresses cell cycle by inhibiting the polyamine synthesis through binding to the rate limiting enzyme ornithine decarboxylases (ODC). High levels of ODC have been reported in several forms of cancer, among them prostate cancer. Antizyme Inhibitor (AZIN) binds to antizyme and thereby blocks its inhibitory effect on ODC. Here, we have measured the expression and localization of AZIN in 202 prostate cancer specimens, along with 26 adjacent benign samples and found that nuclear localization of AZIN is associated with significantly lower survival. Upregulation and nuclear localization of AZIN have been observed in several cancers, as has editing of the AZIN1 mRNA. Others have hypothesized that the RNA- edited AZIN (edAZIN) may have an increased affinity to antizyme and that could explain the association of edAZIN to the various cancers. We have studied the mechanism behind the nuclear localization of AZIN and found the single base pair substitution caused by RNA editing is sufficient to result in nuclear localization of the protein in all cell types tested. To determine if the nuclear localization might result from increased antizyme-edAZIN affinity, we developed fluorescent protein FRET sensor for protein-protein interaction using Clover-AZIN and antizyme-mRuby2 fusion proteins. Unexpectedly, we found that the editing event modestly decreases edAZIN affinity for antizyme, notwithstanding increased interaction in vivo. Thus, the data indicate that the change in protein localization to the nucleus may be more important to oncogenic function than the actual degree of binding to antizyme. Other functional differences between edAZIN and AZIN might be explained by altered kinetics of binding, by the contribution of an additional adapter protein which modulates the intracellular antizyme:AZIN complex, or by competition for AZIN binding by other partners whose interaction is affected by the editing event. Finally, we identified AZIN and edAZIN interacting proteins by using tandem affinity purification and LC-MS-MS analysis. Among interacting proteins, we identified a complex containing two isoforms of nuclear actins (ACTG1 and ACTA2) and Myosin-9 that may be the driving force behind the nuclear shuttling of edAZIN.
Citation Format: Aram Ghalali, James M. Rice, Liangzhe Wang, Chin Lee Wu, Michael S. Rogers, Bruce Zetter. Nuclear localization of antizyme inhibitor may be a marker for aggressiveness of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4888.
Abstract 492: Spatial overlap analysis of myeloid and T cell compartments identifies distinct subgroups in the cohort of selected colorectal primary tumors
Authors: Zwing Natalie , Canamero Marta , Gaire Fabien , Korski Konstanty 
Published: August 2019

Abstract
The immune contexture of colorectal cancer (CRC) tumors classifies clinically relevant immune subtypes that are extensively studied. Recent developments in digital computational pathology supporting spatial characterization of tumor immune infiltrate allow more comprehensive analysis of relevant cell to cell interactions. Leveraging that methodology in the current study, we tried to address the question how the distribution of myeloid cells in the tumor microenvironment (TME) of CRC affects the effector functions and distribution of cytotoxic T cells.
We applied multicolored immunohistochemistry to identify monocytic (CD11b/CD14) and granulocytic (CD11b/CD15) myeloid cell populations together with proliferating and non-proliferating cytotoxic T cells (Ki67/CD8). Through automated object detection and image registration using HALO software (IndicaLab), we measured the extent of overlap between the areas occupied by myeloid and T cells. Subsequently, we correlated it with other parameters such as CD8 T cell proliferation ratio, amount of necrosis, MMR status, tumor mutational burden and CMS classes. With this approach, we identified distinct categories of CRC based on the myeloid - T cell overlap irrespective of the MMR status. These categories reflect certain functional areas in the TME and correlate with specific gene signatures that mainly include T effector and memory together with myeloid inflammatory and immunosuppressive signatures.
Our results emphasize the importance of analyzing spatial organization of immune infiltrate in TME and shed a new light on myeloid and T cell interactions in CRC. The approach we used has a potential to be applied in immunotherapy related biomarker studies.
Citation Format: Natalie Zwing, Marta Canamero, Fabien Gaire, Konstanty Korski. Spatial overlap analysis of myeloid and T cell compartments identifies distinct subgroups in the cohort of selected colorectal primary tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 492.
Abstract 4921: TGF-beta signaling proteins and CYP24A1 may serve as surrogate markers for progesterone calcitriol treatment in ovarian and endometrial cancers of different histological types
Authors: Paucarmayta Ana , Taitz Hannah , Casablanca Yovanni , Rodriguez Gustavo C. , Maxwell G L. , Darcy Kathleen M. , Syed Viqar 
Published: August 2019

Abstract
Strategies are needed to coordinately block drivers and induce suppressors of cancer to reduce incidence and improve outcomes for individuals with inherited or acquired risk. We previously reported the chemopreventive and therapeutic efficacy of the combination of progestin and calcitriol in transformed and malignant endometrioid endometrial cancer and in ovarian cancer models involving attenuated expression of TGF-β signaling proteins and progestin-mediated inhibition of calcitriol-induced CYP24A1 expression. This study aims to expand the applications for this combination to other subtypes of endometrial and ovarian cancers including those with mutations in ARID1A or PIK3CA, DNA mismatch repair deficiency or BRCA1-null status. The end points for this in vitro investigation included assessments of cell growth and the expression of TGF-β ligands, receptors, SMAD proteins and CYP24A1. Treatment of ovarian clear cell carcinoma, endometrioid carcinoma, papillary serous adenocarcinoma, BRCA1 null, and DNA mismatch repair deficient endometrial cancer cell lines with progesterone alone or in combination with calcitriol inhibited cell growth and expression of TGF-β1, TGF-β2, TGF-Rβ1, TGF-βR2, pSMAD2/3 and CYP24A1. Expression of TGF-βR3, SMAD-4, PR and VDR was not altered in any cell line tested except, ES-2, where VDR expression was upregulated in response to treatment. These results suggest that progesterone alone and progesterone-calcitriol combination have broad application in both chemopreventive and therapeutic settings that merit further development in a wide variety of ovarian and endometrial cancers, including those derived from germline or somatic mechanisms. Moreover, our data suggest that TGF-β signaling proteins and CYP24A1 may be effective surrogate markers indicative of treatment response.
Citation Format: Ana Paucarmayta, Hannah Taitz, Yovanni Casablanca, Gustavo C. Rodriguez, G L. Maxwell, Kathleen M. Darcy, Viqar Syed. TGF-beta signaling proteins and CYP24A1 may serve as surrogate markers for progesterone calcitriol treatment in ovarian and endometrial cancers of different histological types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4921.