bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3024: Targeting TMEPAI/PMEPA1 inhibits triple negative breast cancer cell growth and metastasis by enhancing growth suppressive TGF-β signaling
Authors: Singha Prajjal Kanti , Pandeswara Srilakshmi , Venkatachalam Manjeri A. , Saikumar Pothana 
Published: July 2016

Abstract
Triple negative breast cancers (TNBC) that lack estrogen receptor (ER), progesterone receptor (PR) and hormone epidermal growth factor receptor 2 (HER-2/neu) are aggressive and cause high mortality among breast cancer patients. Transforming growth factor beta (TGF-β) dependency for their aggressive behavior (growth and metastasis) has been well established in many of these tumors. Although targeting TGF-β signaling has major potential to treat TNBCs, however it carries the risk of disturbing the tumor suppressive effects of TGF-β in early tumors and its homeostatic control of normal tissues. Hence there is a need to identify novel targets to impede tumor progression without compromising the beneficial effects of TGF-β signaling. To satisfy this unmet need, earlier we identified that transmembrane prostate androgen induced (TMEPAI/PMEPA1), a direct target gene of TGF-β could act as a “molecular switch” that converts TGF-β from a tumor suppressor to promoter in TNBC. Thus, we undertook the present study that identified a novel compound that blocked TMEPAI expression.
We identified terpenoid derivatives (TD) which inhibited the expression of TMEPAI, enhanced TGF-β signaling and blocked proliferation, migration and invasion of several triple negative breast cancer cells in vitro. Our results showed that TD increased phosphorylation of Smad2/3 and increased PTEN, p21 and p27 proteins that cause growth suppression. Concomitantly, TD decreased Akt phosphorylation and reduced Snail and Slug that are required for cell growth and metastasis. Interestingly, TD did not affect the growth of normal human mammary epithelial cells and failed to cause associated molecular changes that can result in growth suppression. Notably, using mice models (nude mice and syngeneic BALB/c mice), we showed that TD reduced tumor burden significantly with little or no toxicity. Consistent with its ability to inhibit Akt phosphorylation and induction of Snail and Slug proteins, TD suppressed lung metastasis of TNBC in mice model. Importantly, reduced tumors derived from TD treated mice exhibited increased expression of pSmad2/3, PTEN, p21, p27 and reduced expression of pAkt compared to tumors obtained from vehicle treated mice. These results suggest that drugs that target TMEPAI will restore homeostatic functions of TGF-β to inhibit growth and metastasis of TNBC and thus prevent new tumor development.
Citation Format: Prajjal Kanti Singha, Srilakshmi Pandeswara, Manjeri A. Venkatachalam, Pothana Saikumar. Targeting TMEPAI/PMEPA1 inhibits triple negative breast cancer cell growth and metastasis by enhancing growth suppressive TGF-β signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3024.
Abstract 3068: Anti-tumor effect of DHP107, a mucoadhesive lipid formulae of oral paclitaxel, in bladder cancer model
Authors: Kim Se Hyun , Kim Jung Min , Kim Tae Soo , Lee Won Suk , Kwon Woo Sun , Lim Seung Tak , Ahn Joong Bae , Kim Se-Kyu , Jo Yeong Woo , Rha Sun Young 
Published: July 2016

Abstract
Purpose: Paclitaxel is an effective anti-neoplastic agent in many solid tumors including bladder cancer. With the development of new drug delivery strategies, novel formulations of Cremophor EL-free paclitaxel have been developed. Here, we investigated the in vitro and in vivo anti-tumor effect of a mucoadhesive oral formulation of paclitaxel (DHP107) in comparison with iv paclitaxel in a human bladder cancer model.
Methods: Four human bladder cancer cell lines (RT4, T24, J82, HT1376) and one murine bladder cancer cell line (MBT-2) were used in this study. In vitro antitumor activity and underlying mechanisms were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, cell-cycle analysis and apoptosis assay. In the in vivo study, RT4 cell line was implanted subcutaneously in the flank of nu/nu mice, and treated with iv paclitaxel and 2 doses of DHP107. The effects were assessed by the tumor growth, body weight and Ki-67 staining in tumor tissues.
Results: The IC50 values of DHP107 ranged from 4.15 to 34.72 μg/ml with MTT assay. In RT4 cell line, both drugs induced similar G2-M arrest and apoptosis. The xenograft experiments showed that both DHP107 (per os, 50 mg/kg, equivalent of paclitaxel 10 mg/kg) and iv paclitaxel (intraperitoneal, 10 mg/kg) attenuated the growth of RT4 tumors in mice, equivalently. The higher dose (per os, 100 mg/kg) of DHP107 resulted in increased efficacy compared with the lower dose (50 mg/kg) without weight loss in mice. However, significant weight loss was observed in iv paclitaxel (-20% at Day 11) treated group. We observed significantly decreased proliferation with Ki-67 staining in DHP107 (100 mg/kg) treated group than in DHP107 (50 mg/kg) or iv paclitaxel (10 mg/kg) treated groups.
Conclusion: Our findings provide the evidence that DHP107 showed comparable antitumor effect with iv paclitaxel and is a promising anti-tumor agent in bladder cancer. Clinical studies in patients with bladder cancer warrant further investigation.
Citation Format: Se Hyun Kim, Jung Min Kim, Tae Soo Kim, Won Suk Lee, Woo Sun Kwon, Seung Tak Lim, Joong Bae Ahn, Se-Kyu Kim, Yeong Woo Jo, Sun Young Rha. Anti-tumor effect of DHP107, a mucoadhesive lipid formulae of oral paclitaxel, in bladder cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3068.
Abstract 3080: OPB-51602: a novel STAT3 inhibitor that targets mitochondrial respiratory chain and triggers STAT3 dependent ROS production
Authors: Hirpara Jayshree L. , Higuchi Kumi , Tsunoda Takeshi , Goh Boon Cher , Pervaiz Shazib 
Published: July 2016

Abstract
Signal transducer and activator of Transcription (STAT) proteins are activated upon extracellular signals resulting in their phosphorylation and nuclear translocation. Once in the nucleus, STAT proteins, in specific STAT3 activates gene transcription of factors involved in a myriad of cellular processes, including proliferation and survival. By implication, increased expression and activity of STAT3 are associated with human cancers, which argue strongly for the development of STAT inhibitors as a promising chemotherapeutic strategy. We are working with a novel STAT3 inhibitor, OPB-51602, that not only block STAT3 phosphorylation but also inhibits growth and colony formation in a variety of human cancer cell lines. Of note, in addition to targeting STAT3, the compound inhibits mitochondrial respiratory chain and triggers a significant increase in mitochondrial superoxide (O2-) production (within 1 hour of exposure) in NSCLC cell line H1975. Using functional mutants of pY705 and pS727 STAT3, the growth inhibitory activity of the compound could be compromised, however, only S727 mutant rescued the mitochondrial effects. In addition, exposure of cells to OPB-51602 resulted in extracellular acidification (ECAR) together with a complete shutdown of mitochondrial ATP production. Interestingly, these effects could be rescued by 2-deoxyglucose. These data provide evidence that the pharmacological inhibition of STAT3 not only blocks cell proliferation but also induces mitochondrial redox catastrophe and bio-energetic crisis, which could have potential therapeutic implications against cancers that are rendered drug resistant due to the activation of surrogate STAT3 signaling axis.
Citation Format: Jayshree L. Hirpara, Kumi Higuchi, Takeshi Tsunoda, Boon Cher Goh, Shazib Pervaiz. OPB-51602: a novel STAT3 inhibitor that targets mitochondrial respiratory chain and triggers STAT3 dependent ROS production. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3080.
Abstract 3237: Assessment and targeting of M2-tumor associated macrophages (M2-TAMs) in prostate cancer
Authors: Zarif Jelani C. , Henandez James R. , Pienta Kenneth J. 
Published: July 2016

Abstract
Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth, progression and metastasis. The central hypothesis of this study is to determine if targeting of M2-TAMs using specific surface antigens will be an effective therapy for lethal prostate cancer and potentially, other cancers. Our study elucidated M2-Macrophage biology including creating homogenous populations of both M1 and M2 macrophages using a new strategy as to allow for identification of novel surface antigen markers. While using our new method for polarization of human monocyte polarization into macrophages, we found that M2 macrophages polarization was stymied in vitro after glutamine deprivation. We then assessed novel markers of macrophage populations, cytokine and chemokine production, T-Cell inactivation and we also assessed whether these surface antigens that are expressed on M2-macrophages are were found in metastatic human prostate cancers indicative of myeloid infiltration. Validation studies using metastatic prostate cancer tissues from rapid autopsies and surgical specimens supplied by the Department of Urology at Johns Hopkins University School of Medicine were also be performed. Complementary studies will be executed to target these markers for anti-tumor cell efficacy using these relevant model systems. By identifying and targeting specific markers on M2-TAMs, we predict that this targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer.
Citation Format: Jelani C. Zarif, James R. Henandez, Kenneth J. Pienta. Assessment and targeting of M2-tumor associated macrophages (M2-TAMs) in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3237.
Abstract 3437: Cancer and all-cause mortality among white and blue collar workers in middle-aged and elderly chinese women in a prospective cohort study
Authors: Ji. Bu-Tian 
Published: July 2016

Abstract
Inequalities in health and mortality between white and blue collar workers have been well documented in western countries, particularly among men. Studies regarding occupation related mortality disparities in Asian populations including Chinese are limited. We included 74,941 40-70 years old Chinese women from the Shanghai Women's Health Study (SWHS) in an analysis of occupation and mortality. An in-person interview was conducted at enrolment to obtain lifetime job history as well as lifestyle and other potential risk factors for each participant. Each job title was coded in three digits according to the Chinese National Standard Occupation and Industry Codes Manual, and the categories of white and blue collar work were defined based on this coding. The information on mortality was provided by annual linkage to the Shanghai Vital Statistics Registry. Cox regression models were applied to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cause-specific mortality. In comparison with lifetime white collar workers, lifetime blue collar workers had 18% excess in all cause-mortality (HR = 1.18, 95% CI = 1.04-1.34) and 12% excess in cancer deaths (HR = 1.12, 95% CI = 0.93-1.35) after adjustment for lifestyle and other potential risk factors. A significantly increased risk was also associated with mortality from diabetes (HR = 1.89, 95% CI = 1.06-3.37). There were no statistically significant differences in mortality between white and blue collar workers for other causes of death including circulatory, respiratory, gastrointestinal or other diseases among this population. Our study provides suggestive evidence that blue collar workers may have a higher risk of total cancer mortality compared to white collar workers among women in Shanghai.
Citation Format: Bu-Tian Ji. Cancer and all-cause mortality among white and blue collar workers in middle-aged and elderly chinese women in a prospective cohort study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3437.
Abstract 3521: The effect of MazF, Escherichia coli ribonuclease, on gastric adenocarcinoma (AGS cells)
Authors: Saffarian Maryam , Tzeng Jeremy 
Published: July 2016

Abstract
Apoptosis is a gene-directed program that could be inhibited by several factors such as the disruption of the balance between pro-apoptotic and anti-apoptotic proteins, the impaired death receptor signalling or the reduced caspase functions. Several studies have shown that ribonucleases or antibiotics can induce apoptosis in mammalian cells through the shutoff of the protein synthesises. MazF produced by E. coli is a ribonuclease protein that cleaves mRNAs at ACA sequence sites and inhibits their translation. Thus, we hypothesized that the overexpression of MazF proteins in cancer cells could lead to the induction of apoptosis. In the present study, the ACA-less mazF gene was inserted into pSF-T7-EMCV T7 IRES expression plasmid. The mRNAs of mazF gene were synthesized in in vitro conditions, and one μg/ml of the mRNA was transferred into AGS (Gastric adenocarcinoma) cell line. The incidence of apoptosis was detected by conducting caspase 3/7 and Annexin-V assays. The results showed that 99.83% of cells were detached after 18 hours, 0.0086% of cells remained attached without apparent apoptosis, but 0.101% of attached cells were under apoptotic conditions. The results suggest that MazF protein has an ability to induce apoptosis in AGS cells. Since this protein can cleave mRNAs at ACA sites, it could inhibit protein synthesis, reduce the growth rate, and induce apoptosis in cancer cells. This finding is the first report of the application of MazF as an anti-cancer agent for the induction of apoptosis in AGS cell line.
Citation Format: Maryam Saffarian, Jeremy Tzeng. The effect of MazF, Escherichia coli ribonuclease, on gastric adenocarcinoma (AGS cells). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3521.
Abstract 3572: AZ5576, a novel potent and selective CDK9 inhibitor, induces rapid cell death and achieves efficacy in multiple preclinical hematological models
Authors: Cidado Justin , Shen Minhui , Grondine Michael , Boiko Scott , Wang Haiyun , Borodovsky Alexandra , Mazzola Anne Marie , Wu Alan , Lawson Deborah , Ferguson Douglas , Gao Beirong , Cui Andy , D’Cruz Celina , Drew Lisa 
Published: July 2016

Abstract
Cyclin-dependent kinase 9 (Cdk9) is a serine/threonine kinase that regulates elongation of transcription through phosphorylation of RNA polymerase II at serine 2
(pSer2-RNAPII). Mcl1, an anti-apoptotic protein that has been linked to increased survival and chemotherapy resistance in various cancers, can be indirectly modulated through transient inhibition of Cdk9 due to it having a short-lived transcript and being a labile protein. Transient inhibition of Cdk9, therefore, represents a potential therapeutic opportunity in tumors dependent on Mcl1 for survival, including various hematological malignancies. AZ5576 is a potent, highly selective, and orally bioavailable inhibitor of Cdk9 that inhibits Cdk9 enzyme activity with an IC50 &lt;5nM and decreases phosphorlyation of Ser2-RNAPII in cells with an IC50 of 96nM. In the MLL-fusion containing acute myeloid leukemia (AML) line, MV411, short-term treatment with AZ5576 led to a rapid dose-dependent decrease in pSer2-RNAPII with concomitant loss of Mcl1 mRNA and protein, resulting in the cleavage and activation of caspase 3 and loss of cell viability. However, protein expression of other Bcl2 family members (e.g. Bcl2, BclxL, Bim) remained unchanged. Further, AZ5576 induced rapid caspase activation and loss of viability in a diverse set of hematological cancer cell lines, including those from acute myeloid leukemia (16/20), multiple myeloma (10/19), and diffuse large B-cell lymphoma (8/13). In vivo efficacy with intermittent dosing of AZ5576 was also demonstrated in multiple xenograft models from each hematological tumor type. Finally, AZ5576 was still able to induce loss of viability in various multiple myeloma lines cultured in the presence of cytokines or bone marrow stromal cells that represent potential protective effects of the tumor microenvironment. Together, these results highlight the therapeutic potential for selective CDK9 inhibition in the treatment of hematological malignancies.
Citation Format: Justin Cidado, Minhui Shen, Michael Grondine, Scott Boiko, Haiyun Wang, Alexandra Borodovsky, Anne Marie Mazzola, Alan Wu, Deborah Lawson, Douglas Ferguson, Beirong Gao, Andy Cui, Celina D’Cruz, Lisa Drew. AZ5576, a novel potent and selective CDK9 inhibitor, induces rapid cell death and achieves efficacy in multiple preclinical hematological models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3572.
Abstract 3622: Complete workflow for detection of low frequency somatic mutations from cell-free DNA using Ion Torrent™ platforms
Authors: Gu Jian , Brinza Dumitru , Mongan Ann , Chien Richard , Dhingra Dalia , Hyland Fiona , Bramlett Kelli 
Published: July 2016

Abstract
Research detecting of somatic mutations in circulating cell-free DNA (cfDNA) using research blood samples from subjects previously diagnosed with cancer provides a potential non-invasive approach to monitor cancer status and evaluate cancer evolution in the future. However, most of the existing mutation detection methods show insufficient sensitivity to detect cfDNA mutations since only small amount of mutant gene fragments, derived from tumor cells, is present in a large amount of normal circulating DNA background.
We demonstrated a complete workflow that includes blood collection, cfDNA isolation, library preparation, sequencing, and data analysis to enable detection of rare DNA variants in blood plasma samples. Blood samples were collected using Streck™ DNA tubes followed by plasma preparation and cfDNA isolation using MagMAX™ Cell-Free DNA Isolation Kit. Library preparation was performed using Oncomine™ lung cfDNA kit. Barcoded libraries were pooled and sequenced on Ion Torrent™ Next Generation Sequencing Platforms. Sequencing data was analyzed in Torrent Suite™ using variantCaller-cfDNA plugin. ∼150 biomarkers relevant to non-small cell lung cancer were interrogated in one sequencing run.
We demonstrated detection sensitivity at 0.1% frequency using engineered mutants that were spiked into control DNA samples. The workflow was tested on a set of research samples from matched tumor FFPE and blood plasma collected from research subjects with non-small cell lung cancer (NSCLC). About 1 mL of plasma was processed using the workflow described above. RecoverAll™ Multi-Sample RNA/DNA Isolation Workflow was used to isolate DNA from FFPE samples, followed by library preparation, sequencing and data analysis using the same workflow described above. Summary of variant calls from matched cfDNA and FFPE tumor samples are presented here. Results indicate high sensitivity of the workflow and expected levels of concordance between variants detected in the two types of research samples.
In this study, we developed a highly sensitive and reliable research workflow to detect rare somatic mutations in circulating cfDNA samples. Significant overlapping of mutations discovered in FFPE tumor and cfDNA samples suggests that this workflow may be used to monitor tumor dynamics in NSCLC and potentially other tumors in the future.
Disclaimer: For research use only. Not for use in diagnostic procedures.
Citation Format: Jian Gu, Dumitru Brinza, Ann Mongan, Richard Chien, Dalia Dhingra, Fiona Hyland, Kelli Bramlett. Complete workflow for detection of low frequency somatic mutations from cell-free DNA using Ion Torrent™ platforms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3622.
Abstract 3643: Flow cytometry multiplexing used to analyze metabolic activity and assess pharmaceutical compound toxicity as a high throughput screening tool
Authors: OGrady Mike , Montoya Leticia A. , Yan Michelle , Clarke Scott T. , Low Quentin , DeMarco Carolyn , Anderson April , Kihn Kathy , Finnessy Carmen , Wickett Marcy , Calderon Veronica 
Published: July 2016

Abstract
High throughput screening (HTS) is an extremely effective method for allowing researchers to identify putative active compounds for therapeutics. Recently, flow cytometry has emerged as a powerful HTS tool with the added benefit of cell-by-cell analysis. Flow cytometry allows a researcher to study protein-protein interactions, metabolic activities, as well as DNA content in a single or multiplexed assay format. For this study, we screened the Tocriscreen Total compound library and compared HTS using a plate reader with flow cytometer multiplexing.
Peripheral blood mononuclear (PBMCs) and Jurkat cells were used as cell models. Cells were cultured under standard conditions and either at normoxic (5%) or hyperoxic (19%) oxygen levels. We also varied length of time the cells were treated with compound library (24, 48, or 72 hrs). Membrane integrity and metabolic activity were measured as an output for evaluating cellular viability. To further assess cellular activity, post-screening analysis was implemented to establish EC50s of “hits” from compound library.
Screening analysis identified target drugs that were further analyzed using cell health readouts with different mechanisms of action to assess compound toxicity. Results indicate that compound “hits” and potency differed in the screen depending on cell type, the mechanistic readout, length of compound exposure, and mode of readout used to perform the HTS experiments.
Citation Format: Mike OGrady, Leticia A. Montoya, Michelle Yan, Scott T. Clarke, Quentin Low, Carolyn DeMarco, April Anderson, Kathy Kihn, Carmen Finnessy, Marcy Wickett, Veronica Calderon. Flow cytometry multiplexing used to analyze metabolic activity and assess pharmaceutical compound toxicity as a high throughput screening tool. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3643.