bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 188: Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice
Authors: Zhang Qi , Pan Jing , Miller Marker S. , Lubet Ronald A. , Wang Yian , You Ming 
Published: July 2017

Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States. The 5 year survival rate for lung cancer patients has remained a dismal 15% for 3 decades. Thus, the development of chemopreventive agents that could prevent lung cancer could potentially reduce the incidence and mortality of pulmonary neoplasms. Bexarotene has exhibited inhibitory effects in preclinical in vivo models of mammary and lung tumorigenesis, has been approved for clinical use in the treatment of cutaneous T-cell lymphoma, and has shown efficacy in phase I/II trials of non-small cell lung cancer (NSCLC). Preclinical studies have demonstrated that it is highly effective in the prevention of all three major subtypes of lung cancer in mouse models: adenocarcinoma (AD), squamous cell carcinoma (SCC), and small cell lung cancer (SCLC). The major side effects of bexarotene when administered orally to rodents or human patients have been hypertriglyceridemia and hypercholesterolemia. Previous studies in a mouse model of lung AD have demonstrated that aerosol delivery of bexarotene through nasal inhalation exhibited potent chemopreventive activity similar to that observed following oral administration (59 to74% reductions in lung tumor multiplicity). The significant decreases in tumor multiplicity and tumor load were achieved without hypertriglycerides that accompany oral bexarotene administration. In this study, aerosolized delivery of 10-30 mg/ml bexarotene showed a significant chemopreventive effect in all three major subtypes. In the N-nitroso-tris-chloroethylurea (NTCU) induced mouse SCC model, 1 week after the first dose of NTCU a dose dependent decrease in tumor formation was observed, with the highest dose causing 75% (p&lt;0.001) and 42% (p&lt;0.01) decreases in SCC tumor burden and the percentage of SCC tumors, respectively. Tumor load was decreased by 73% in A/Jp53 mouse AD model and by 41% in A/Jp53Rb mouse SCLC model. Aerosol delivery of bexarotene had no effect on animal body weight and other signs of toxicity, and no effect on triglyceride and cholesterol level. Aerosolized bexarotene formulation was effective against all 3 major lung cancer cell types and would be a major advance achieving significant reductions in preventing lung cancer incidence in persons at high risk of lung cancer e.g. former or present smokers.
Citation Format: Qi Zhang, Jing Pan, Marker S. Miller, Ronald A. Lubet, Yian Wang, Ming You. Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 188. doi:10.1158/1538-7445.AM2017-188
Abstract 1967: A novel 40kDa CPE-ΔN isoform promotes proliferation and invasion in pancreatic cancer cells
Authors: Yang XuYu , Ling Cong , Lou Hong , Peng Loh Yoke 
Published: July 2017

Abstract
Carboxypeptidase E (CPE) is a prohormone processing exopeptidase that cleaves C-terminal basic residues from peptide hormones liberated endoproteolytically from prohormones. It is a 476- amino acid protein with a signal peptide in its N-terminus and is mainly expressed in neuropeptide-rich areas of brain and endocrine tissues. As a multifunctional protein, CPE plays many non-enzymatic roles such as prohormone sorting, vesicle transport, and secretion in addition to its carboxypeptidase activity. Moreover, high expression of CPE is found in metastatic tumor tissues, including liver cancer, renal clear cell carcinoma, colorectal cancer, cervical cancer and melanoma, suggesting CPE may be involved in tumor metastasis and progression. In this study, a novel CPE splice isoform mRNA was identified by Northern blotting, which is ~1.83kb in size. RACE assay and sequence analysis confirmed existence of this CPE isoform mRNA, which partially lacks a N-terminus region, and has a shorter 3’-UTR compared to WT-CPE mRNA, by removal of 188 nucleotides within the first exon and 589 nucleotides out of the 3’-UTR, respectively. Bioinformatics analysis revealed that this CPE isoform mRNA has a shortened ORF, which starts coding from the 3rd ATG relative to wild-type (WT) CPE mRNA and encodes a 40kDa CPE-αN protein with the N-terminus truncated. Western blot analysis showed that 40kD CPE-αN is expressed in multiple cancer cell lines and tumor tissues. In Panc-1pancreatic cancer cells, knockdown of endogenous CPE(s) inhibited cell growth and invasion; in contrast, ectopic expression of 40kD CPE isoform significantly promoted proliferation, colony formation, invasion and migration, whereas overexpression of WT-CPE had only a small effect. These results suggest that the 40kD CPE-αN isoform plays a role in cell growth and metastasis.
Note: This abstract was not presented at the meeting.
Citation Format: XuYu Yang, Cong Ling, Hong Lou, Loh Yoke Peng. A novel 40kDa CPE-ΔN isoform promotes proliferation and invasion in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1967. doi:10.1158/1538-7445.AM2017-1967
Abstract 199: Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways
Authors: Imai-Sumida Mitsuho , Chiyomaru Takeshi , Majid Shahana , Kulkarni Priyanka , Dasgupta Pritha , Saini Sharanjot , Kato Taku , Maekawa Shigekatsu , Hashimoto Yutaka , Shiina Marisa , Deng Guoren , Shahryari Varahram , Nip Hannah , Dahiya Rajvir , Tanaka Yuichiro , Yamamura Soichiro 
Published: July 2017

Abstract
Silibinin is the major active constituent of silymarin, an extract of milk thistle seeds. Silibinin has been shown to have significant anti-cancer effects in a variety of malignancies. However, the molecular mechanisms of silibinin action in bladder cancer have not been studied extensively. In the present study, we found that silibinin (10 μM) significantly suppressed proliferation and invasion of T24 and UM-UC-3 human bladder cancer cells. In this study, we investigated the molecular mechanisms underlying these effects of silibinin. Our results showed that silibinin down-regulates actin cytoskeleton-related Ras-Rac-PAK1 pathways and the phosphatidylinositide 3-kinase (PI3K)/Akt signaling pathway in these bladder cancer cell lines. These pathways were found to promote cellular transformation and cancer development and have crosstalk through Ras cascades. We investigated the role of silibinin on Ras, and found that silibinin suppresses levels of trimethylated histone H3 lysine 4 and acethylated H3 at the K-RAS promoter. We also found that silibinin downregulates long non-coding RNAs: HOTAIR and ZFAS1, which are known to play roles as oncogenic lncRNAs in various cancers. This study shows that silibinin exerts anti-cancer effects through down-regulation of the actin cytoskeleton and PI3K/Akt pathways and thus suppresses the development and progression of bladder cancer.
Citation Format: Mitsuho Imai-Sumida, Takeshi Chiyomaru, Shahana Majid, Priyanka Kulkarni, Pritha Dasgupta, Sharanjot Saini, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Guoren Deng, Varahram Shahryari, Hannah Nip, Rajvir Dahiya, Yuichiro Tanaka, Soichiro Yamamura. Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 199. doi:10.1158/1538-7445.AM2017-199
Abstract 2023: Artemisinins enhanced the antileukemic efficacy of BCL2 inhibitors
Authors: Moses Blake S. , Fox Jennifer M. , Chen Xiaochun , Tyner Jeffrey W. , Posner Gary H. , Bailey Patrick , Civin Curt I. 
Published: July 2017

Abstract
More effective, less toxic treatments are needed to improve longevity and quality of life for patients with acute leukemias. Artesunate (AS), the current WHO-recommended drug for severe malaria, is a semi-synthetic derivative of the natural compound Artemisinin. AS has broad antineoplastic activity in vitro, and is well tolerated, inexpensive, and can be parenterally or orally administered in humans. Both AS and a more potent synthetic derivative, artemisinin-derived trioxane diphenylphosphate dimer 838 (ART-838), substantially inhibited acute leukemia growth in vivo and in vitro, at doses where normal CD34+ hematopoietic stem-progenitor cell clonogenicity was essentially unaffected. Moreover, AS and ART-838 synergized with several current antileukemic drugs (Fox et al, Oncotarget, 2015). To identify additional potential antileukemic drug combinations, we screened for the growth inhibitory effects of AS and ART-838 against 3 acute leukemia cell lines co-treated with a panel of 122 antileukemic compounds (mainly emerging antineoplastic drugs). Both AS and ART-838 showed synergistic or additive growth inhibition with several compounds. Two BCL2 protein family inhibitors demonstrated among the highest levels of synergy. One of these, ABT-199 (venetoclax), was recently approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL) and received breakthrough designation for acute myeloid leukemia (AML). Therefore, we decided to further investigate the combination of ABT-199 with AS or ART-838. Synergy between AS (or ART-838) and ABT-199 was confirmed across several acute leukemia cell lines with varying sensitivities to each drug. Both leukemia cell proliferation and survival were affected synergistically by exposure to the combination of AS (or ART-838) plus ABT-199. Utilizing in vivo imaging, we assessed changes in growth kinetics of tail vein-injected acute leukemia cell lines and primary patient-derived samples constitutively expressing luciferase in mice treated with AS, ABT-199, or the combination. The combination of AS plus ABT-199 had the greatest antileukemic effect. Based on these data, we propose that Artemisinins plus BCL2 inhibitors comprise an antileukemic drug pair with high potential for incorporation into acute leukemia therapeutic regimens.
Citation Format: Blake S. Moses, Jennifer M. Fox, Xiaochun Chen, Jeffrey W. Tyner, Gary H. Posner, Patrick Bailey, Curt I. Civin. Artemisinins enhanced the antileukemic efficacy of BCL2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2023. doi:10.1158/1538-7445.AM2017-2023
Abstract 2088: The activity of the FGFR selective inhibitor Debio 1347 is correlated with high mRNA expression
Authors: Brichory Franck , Pokorska-Bocci Anna , Nuciforo Paolo , Rigotti Stefania , Lembrez Nathalie , Vuagniaux Grégoire , Moulon Corinne , Vaslin Anne 
Published: July 2017

Abstract
Dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway due to receptor overexpression, gene amplification, point mutations or fusions/chromosomal translocations is associated with cancer development and progression.
Debio 1347 (CH5183284) is an oral selective FGFR inhibitor (FGFR1, 2 and 3) currently in clinical development. The aim of this study was to investigate Debio 1347 activity in patient derived xenograft (PDX) mouse models harboring diverse FGFR alterations in multiple indications.
The trial was conducted in 66 PDX models of diverse histotypes selected according to their FGFR1, 2 and 3 alteration status. Debio 1347 was administered orally once daily at 40 up to 80 mg/kg for 10 to 22 consecutive days (N=3/group). Tumor volume was compared to the vehicle control group and measured by caliper twice weekly. Treatment response was determined by relative treatment-to-control ratios (ΔT/ΔC) of which a responding model was defined as ΔT/ΔC &lt;0. PDX tumors were collected at the end of the treatment period and extensively characterized using FISH, nCounter Gene Expression and immunohistochemistry (IHC). Effect on downstream Dual Specificity Phosphatase 6 (DUSP6) signaling was also investigated by qPCR and RNA in situ hybridization (ISH).
Debio 1347 induced tumor regression in 33% of PDX models that exhibited a gene copy number gain and/or the presence of a FGFR fusion gene and/or an FGFR mutation. In addition, Debio 1347 treatment led to tumor regression in 29% of models that did not harbor any FGFR genetic alteration. In contrast, all models that responded to Debio 1347 were shown to display a high expression level (mRNA) of at least one FGFR gene. These findings suggest that high expression of at least one FGFR might be a better predictor of sensitivity to Debio 1347 than genetic alteration. Furthermore, response to Debio 1347 was associated with a decrease in DUSP6 mRNA levels, suggesting that it could be a reliable pharmacodynamic biomarker in clinical trials.
These results provide new mechanistic insights into the predictive sensitivity to Debio 1347 and will help refine patient selection for FGFR-targeted therapy.
Citation Format: Franck Brichory, Anna Pokorska-Bocci, Paolo Nuciforo, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Anne Vaslin. The activity of the FGFR selective inhibitor Debio 1347 is correlated with high mRNA expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2088. doi:10.1158/1538-7445.AM2017-2088
Abstract 2325: Destruction of circulating tumor cells by fluid shear stresses generated in a microfluidic system
Authors: Regmi Sagar , Fu Afu , Lim Sierin , Luo Kathy Qian 
Published: July 2017

Abstract
Circulating tumor cells (CTCs) are mainly responsible for the cause of cancer metastasis. Although most CTCs can be destroyed by the bloodstream, some of them can still manage to withstand hemodynamic shear stress in blood stream. To study the effects of fluidic micro-environment on CTCs, we designed a microfluidic system that can produce various levels of shear stress which can be generated in human artery under resting or exercise condition. We also generated three human breast cancer cell lines with increased ability to form lung metastases in nude mice (i.e. 213-M1A&gt;231-M1&gt;231-C3). All three cell lines can produce a fluorescence resonance energy transfer (FRET)-based sensor which can reveal apoptosis in real-time by changing its color from green to blue. Besides these, we also investigated the effects of shear stress on multiple types of cancer cells including lung cancer (A549), ovarian cancer (2008), breast cancer (UACC-893) and leukemia (K562). For all the cell lines, except the non-attached K562 cells, cells were cultured on petri-dishes, detached by trypsinization and re-suspended in a normal culture medium to a cell density of 2x105 cells/ml. One milliliter of this cell suspensions was circulated in our microfluidic system under the shear stresses of 15, 30, 45 and 60 dyne/cm2 for 2-18 h. The effects of shear stress on morphology and viability of CTCs were determined by FRET imaging microscopy and MTT assay. And the impact of shear stress on causing necrosis in CTCs were examined by propidium iodide (PI) staining and LDH assay. Our findings are summarized below: 1) High shear stress (SS60, 4 h) is more potent to destroy CTCs than low shear stress (SS15, 4 h). 2) High shear stress can destroy most of the CTCs via necrosis. 3) This high level of shear stress is theoretically achievable via physical exercise. 4) Highly metastatic 231-M1A cells are more resistant to high shear stress compared to less metastatic 231-C3 cells. 5) Leukemia K562 cells representing the white blood cells showed stronger resistance to high shear stress compared to the cancer cells tested in this study. We think these findings can help people to understand how metastatic CTCs resist shear force-induced cell death which are useful for designing more effective therapies against metastatic CTCs. Additionally, the finding that high shear stress is more effective to kill CTCs may inspire cancer patients to consider exercise as a way to increase their hemodynamic shear stress, consequently destroy CTCs and prevent cancer metastasis.
Citation Format: Sagar Regmi, Afu Fu, Sierin Lim, Kathy Qian Luo. Destruction of circulating tumor cells by fluid shear stresses generated in a microfluidic system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2325. doi:10.1158/1538-7445.AM2017-2325
Abstract 2369: Transcription activators that regulate PKC-iota expression and are downstream targets of PKC-iota
Authors: Apostolatos Andre H. , Ratnayake Wishrawana S. , Smalley Tracess , Islam Anisul , Acevedo-Duncan Mildred 
Published: July 2017

Abstract
Protein Kinase C-iota (PKC-iota) is an anti-apoptotic oncogene over-expressed in multiple cancers including prostate, ovarian, and glioma. PKC-iota is part of a cycle that helps cancer cell avoid senescence by releasing the transcription factor NFkB and promoting apoptotic resistance. PKC-iota is activated externally by factors like loss of PTEN (Paget 2012). However, while under the effect PKC-iota specific inhibitors, expression levels decreased, suggesting PKC-iota plays a role in regulating its own expression. A previous study showed the ELK1 transcription factor to be a regulator of PKC-iota (Gustafson 2003). Other transcription factors including Jun, ISGF3, PAX3, EGR1, and FOXO1 bind on or near the promoter sequence of the gene and their role in PKC-iota regulation was analyzed. Each transcription factor was systematically silenced with its own siRNA. Western Blotting revealed expression of PKC-iota in the transcription factor silenced cells determining which transcription factors are key players in regulation of PKC-iota. qPCR and microarray were performed to analyze the transcriptome of treated cells to match protein levels with mRNA levels. Targets both up and downstream of PKC-iota were analyzed to find the pathway that PKC-iota uses to help regulate itself.
Citation Format: Andre H. Apostolatos, Wishrawana S. Ratnayake, Tracess Smalley, Anisul Islam, Mildred Acevedo-Duncan. Transcription activators that regulate PKC-iota expression and are downstream targets of PKC-iota [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2369. doi:10.1158/1538-7445.AM2017-2369
Abstract 2508: Profiling the metabolic effects of AGI-5198 treatment on IDH1-mutated gliomas
Authors: Rodado Victor Ruiz , Lita Adrian , Dowdy Tyrone , Gilbert Mark R. , Larion Mioara 
Published: July 2017

Abstract
Background: AGI-5198 (a specific IDH1mut inhibitor) inhibits the formation of D-2-hydroxyglutarate (D-2HG) typically produced in millimolar quantities by the R132H mutation of isocitrate dehydrogenase I (IDH1). AGI-5198 was found to delay growth, to promote differentiation in cells and to decrease tumor volume in IDH1-mutant (IDH1mut) mice xenographs, and as a result, has been advanced to clinical trials in humans with IDH1mut glioblastomas. However, no metabolic study of this drug has been reported to date. Here, we investigated the metabolic changes induced by AGI-5198 treatment in order to determine if the drug restores the normal metabolic status once D-2HG concentration is decreased. Methods: We treated glioma cells carrying an IDH1 mutation with 10 μM AGI-5198 for 72 h. Metabolic changes were explored using an untargeted metabolomics approach. Cell viability analysis verified that the concentration of drug does not lead to significant cell death. NMR and MS-linked metabolomics together with in vivo cell imaging using RAMAN were used. Principal component analysis was employed to explore the differences in the metabolic profiles comparing treated and untreated glioma cells. Results and Conclusions: We confirmed that AGI5198 treatment reduced D-2HG levels in the cell lines investigated, validating previous reports. Moreover, we observed a decrease in phospholipid levels upon AGI-5198 treatment, which suggests a decreased proliferative potential for these cells; of particular importance for clinical application. Our preliminary analysis also suggests that metabolites involved in one carbon metabolism are altered upon AGI-5198 treatment. This pathway provides the methyl group for the DNA methylation by DNA methylases producing a hypermethylated phenotype. Our findings suggest that combining the AGI-5198 treatment with a DNA methylase inhibitor may improve outcomes in IDH1-mutated gliomas.
Citation Format: Victor Ruiz Rodado, Adrian Lita, Tyrone Dowdy, Mark R. Gilbert, Mioara Larion. Profiling the metabolic effects of AGI-5198 treatment on IDH1-mutated gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2508. doi:10.1158/1538-7445.AM2017-2508
Abstract 2578: Investigating the role of mutant p53 in esophageal squamous cell carcinoma
Authors: Lento Ashley , Long Apple , Giroux Veronique , Tang Qiaosi , Sammons Morgan , Klein-Szanto Andres , Berger Shelly , Rustgi Anil 
Published: July 2017

Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer characterized by a high rate of metastasis, limited therapeutic options, and a poor prognosis. However, there is limited information regarding the molecular mechanisms underlying the metastatic properties of ESCC. p53 is one of the most commonly mutated genes in ESCC, and our group has shown that esophageal cells lines expressing a mutation in human p53 shows signs of malignancy and increased invasion in 3D organotypic culture. A mouse model of mutant p53 (R172H) in ESCC is lacking in the field. To elucidate the role of mutant p53 in ESCC we developed a novel mouse model utilizing a genetic and carcinogenic approach. L2cre;p53-/- and p53R172H/- mice were generated and treated with 4NQO in their drinking water for 16 weeks, which resulted in the development of ESCC. Compared to wildtype mice, p53R172H/- mice and p53-/- mice exhibited a decreased tumor latency time, increased tumor frequency and a more severe tumor diagnosis. However, p53R172H/- mice and p53-/- mice displayed similar tumorigenic properties. RNA-seq was performed on cell lines established from wildtype and p53 mouse models and reveled different gene expression profiles between wildtype, p53R172H/-, and p53-/- cells. p53R172H/- cells displayed an increase in mesenchymal and decrease in epithelial marker expression, supporting the idea that they are undergoing EMT. In addition, several endocytic recycling related genes, including Rab11-fip1, Rab25, and Myo5b were downregulated in mutant and null p53 compared to wildtype cells. Further examination of the differing genetic profiles in our mouse models can provide novel insight into the role of mutant p53 in ESCC tumorigenesis and lead to the identification of new therapeutic targets.
Citation Format: Ashley Lento, Apple Long, Veronique Giroux, Qiaosi Tang, Morgan Sammons, Andres Klein-Szanto, Shelly Berger, Anil Rustgi. Investigating the role of mutant p53 in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2578. doi:10.1158/1538-7445.AM2017-2578