bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 44: Characterization and targeting of a temporal micro-metastatic signature in human brain metastases
Authors: Singh Mohini , Venugopal Chitra , Tokar Tomas , McFarlane Nicole , Subhapanditha Minomi , Bakhshinyan David , Qazi Maleeha , Vora Parvez , Savage Neil , Murty Naresh K. , Jurisica Igor , Singh Sheila K. 
Published: August 2018

Abstract
Metastases to the brain (BM) are the most common neoplasms to affect the adult central nervous system, arising in 40% of cancer patients and at a rate 10 times greater than primary brain tumors. Despite the prevalence and poor survival rates, therapeutic strategies for BM remain limited, and a substantial cause is the lack of proper preclinical models available to interrogate the intricacies of BM development. Previous work in our lab utilized BM samples from patient-derived lung-to-brain metastases to successfully establish clinically relevant in vivo models of BM. Here we further characterized the cells responsible for BM, termed brain metastasis initiation cells (BMIC). Patient-derived BMICs were injected via intracranial (BT), intracardiac (IC) and intrathoracic (IT) routes into NOD/SCID mice and re-isolated at different stages of metastatic progression. We isolated cells from primary lung tumors (LT), cells injected via intra-thoracic route that crossed the blood brain barrier to seed the brain forming micro-metastases (BMIT), and cells injected via intracardiac route that seeded large macro-metastases (BMIC). Through RNA sequencing we determined cells from BMIT (micro-metastasis stage) to retain a vastly different genetic profile compared to BMICs isolated at other stages of metastasis. Several of these genes belonged to pathways implicated in autonomic central nervous system neoplasms and neural development. Through connectivity mapping of BMIT profiles we discovered drugs that could inhibit the micro-metatsasis signature, and further in vitro validation revealed apomorphine to reduce BMIC sphere formation and proliferation. In vivo treatment with apomorphine blocked both micro- and macro-metastatic stages of our BMIC model. Of 5 BMIT genes identified to be specifically targeted by apomorphine, KIF16B, TESK2 and SEPW1 were shown to have significant value when applied as an independent prognostic signature in a cohort of lung adenocarcinoma patients. Future work will further validate the efficacy of apomorphine in targeting BMICs in primary lung cancer patient samples. With this work we present a possible new avenue for therapeutic targeting toward the prevention of BM development, where it is anticipated to transform a uniformly fatal disease into one that is eminently more treatable.
Citation Format: Mohini Singh, Chitra Venugopal, Tomas Tokar, Nicole McFarlane, Minomi Subhapanditha, David Bakhshinyan, Maleeha Qazi, Parvez Vora, Neil Savage, Naresh K. Murty, Igor Jurisica, Sheila K. Singh. Characterization and targeting of a temporal micro-metastatic signature in human brain metastases [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 44.
Abstract 4400: MicroRNA loaded circular dumbbell RNAs, a novel antiangiogenic approach
Authors: Gnanamony Manu , lakka Sajani S. , Libes Jaime , Lin Julian , Joseph Pushpa A. , Gondi Christopher S. 
Published: August 2018

Abstract
Angiogenesis is a tightly regulated biological process where new blood vessels are formed from pre-existing blood vessels. This process is also critical in diseases such as cancer; therefore, angiogenesis has been actively explored as a drug target for cancer therapy. Many patients treated with endogenous angiogenesis inhibitors show increased survival; however, eventual resistance to therapies is associated with disease progression and death. The future of effective anti-angiogenic therapy lies in the intelligent combination of multiple targeting agents with novel modes of delivery to maximize therapeutic effects. We therefore propose a novel and ‘out of the box' approach that utilizes dumbbell-RNA (dbRNA) to target pathological angiogenesis by simultaneously targeting multiple molecules and processes that contribute to angiogenesis. Dumbbell RNAs are a stable and safe alternative to viral, non-viral, and naked plasmid-based gene-transfer systems. They integrate the advantages of durable expression that is achievable with integrating viral vectors and short-term effects triggered by naked RNA. In this study, we have successfully constructed a plasmid expressing miR-34a dbRNA using the permuted intron-exon (PIE) method. We have also modified and optimized a cost effective protocol to purifiy dbRNA from bacterial culture with high purity. To test the efficacy of miR-34a dbRNA, we used the pancreatic cancer cell line MIA-PaCa2. When transfected into MIA-PaCa2 cell line we observed increased expression of miR-34a. Further, miR-34a overexpression caused a 3- fold and 2.5-fold decrease in VEGFA and VEGFB RNA expression respectively. Functional validation on the effect of miR-34a on angiogenesis was performed on Human umbilical vein endothelial cells (HUVEC) using the tube formation assay, where miR-34a dbRNA showed significant decrease in tube formation when compared to cells treated with scrambled dbRNA. We will further validate these results in vivo using Zebrafish angiogenesis model. In conclusion, our study demonstrate for the first time a novel approach to block angiogenesis using miR-34a loaded dbRNA. Our data also show that this approach may be used in targeting multiple molecules/pathways, and when used in combination with existing therapies can improve the efficacy of current treatment modalities.
Citation Format: Manu Gnanamony, Sajani S. lakka, Jaime Libes, Julian Lin, Pushpa A. Joseph, Christopher S. Gondi. MicroRNA loaded circular dumbbell RNAs, a novel antiangiogenic approach [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 4400.
Abstract 4404: Identification of small molecules that inhibit miR-21 activity in breast cancer
Authors: Guiraldelli Michel F. , Schwartz Alexander O. , Markus Michelle A. , Jiang Jun , Boyd Justin D. , Radetich Branko , Monahan William E. , Nirmala Nanguneri , Pontin Johan A. , Cohen Dalia 
Published: August 2018

Abstract
In cancer, microRNA (miR) dysregulation can lead to tumor development, invasion and metastasis. miRs are small single-stranded non-coding RNAs that bind to target mRNAs and stop protein expression. miRs are transcribed as a long transcript that fold to form secondary hairpin structures called pri-miRs that are subsequently processed by the microprocessor complex (Drosha and DGCR8) resulting in the formation of the precursor miRs (pre-miRs). Pre-miRs are exported to the cytoplasm via Exportin 5 and RanGTP. In the cytoplasm, pre-miRs are cleaved by Dicer resulting in double stranded molecule. This miR duplex is assembled into the RNA-induced silencing complex (RISC) and targets specific mRNAs. In breast cancer, miR-21 expression levels are increased, and are correlated with tumor grade. The use of small molecules targeting the miR process to modulate levels of mature miR is a novel approach for developing therapeutics. Inactivation of any of the processing steps of miR would result in an inactive mature miR or lower significantly its level. Using a parallel screening approach employing cell biology, NMR and chemistry, we identified several small molecules that bind and inhibit the activity of miR-21. Further characterization of one of our hits in MCF-7 cells showed a dose dependent inhibition of miR-21 activity. A decrease in proliferation with a concomitant increase in apoptosis signal was observed in cells treated with the compound. Analysis of miR-21 processing species by qPCR in MCF-7 cells showed a decrease on pri, pre-and mature miR-21 relative to cells treated with vehicle only. Furthermore, the levels of PDCD4, a direct downstream effector of miR-21, increased upon treatment with the compound. NMR experiments showed that this compound binds to a specific sequence and that the flanking C-G bases are necessary for its binding. These results support the feasibility of targeting miRs by small molecule as a novel therapeutic modality.
Citation Format: Michel F. Guiraldelli, Alexander O. Schwartz, Michelle A. Markus, Jun Jiang, Justin D. Boyd, Branko Radetich, William E. Monahan, Nanguneri Nirmala, Johan A. Pontin, Dalia Cohen. Identification of small molecules that inhibit miR-21 activity in 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 4404.
Abstract 4409: Developing brain tumor-specific gold-liposomal nanocarriers for a noninvasive delivery of microRNA inhibitors
Authors: Grafals Nilmary , Quiñoes-Diaz Blanca I. , Valle Janixa Del , Barletta-Bonano Gabriel L. , Vivas-Mejía Pablo E. 
Published: August 2018

Abstract
MicroRNAs are non-coding RNA molecules that regulate more than 60% of the protein coding genes and their dysregulation has proven to be involved in the initiation, progression and maintenance of malignant brain tumors such as glioblastoma multiforme (GBM). Targeting microRNAs in GBM has shown therapeutic value, although their translation to the clinic have been halted due to their rapid renal clearance, short circulatory life and inability to reach the brain tumor after systemic administration. Over the last years, nanodelivery systems such as liposomes (Lip) and gold nanoparticles (AuNPs) have gained acceptance for the treatment of cancer. This project is focused on developing anti-miRNA gold carriers further encapsulated inside nanoliposomes that are labeled with blood brain barrier specific peptides (Apolipoprotein E and Rabies Virus Glycoprotein). The synthesis of these dual gold-liposomal particles has three important steps: (a) Peptide Pegylation, (b) anti-microRNA conjugation to gold nanoparticles and, (c) nanoparticle assembly. To achieve each of them the corresponding peptide was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)]-Malemide (DSPE-PEG-Mal) by a thioester bond and incorporated into DOPC and cholesterol lipid mixture. Afterwards, anti-microRNAs were functionalized to 15 nm gold nanoparticles (AuNPs) to obtain RNAi-AuNPs. Finally, the nanoparticles of interest where produce: RNAi-AuNP-Lip, RNAi-AuNP-Lip-APOE and RNAi-AuNP-Lip-RVG. These nanoparticles where characterized by dynamic light scattering, zeta potential and encapsulation efficiency. Additionally, we determine their toxicity in U-87 GBM cell lines. Our results obtained show sizes that range from 30 nm, 60 nm and 95 nm for gold-RNAi, gold-liposomes and gold-liposome-peptides respectively. These particles are slightly negative and have encapsulation efficiencies that are greater than 50%. Cell viability analysis also show that gold nanoparticles carrying microRNA inhibitor negative controls are not toxic to GBM cell lines. Additional studies for cell internalization, reactive oxygen species generation and RNA delivery and release are ongoing now. Developing systemic viable microRNA based therapeutics its a big challenge, but they are crucial to assure the patient a non-invasive therapy that could improve their quality of life and their overall survival.
Citation Format: Nilmary Grafals, Blanca I. Quiñoes-Diaz, Janixa Del Valle, Gabriel L. Barletta-Bonano, Pablo E. Vivas-Mejía. Developing brain tumor-specific gold-liposomal nanocarriers for a noninvasive delivery of microRNA inhibitors [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 4409.
Abstract 4414: Radiation-induced miR-5094 expression inhibits cell proliferation by targeting STAT5b
Authors: Ding Nan , Hua Junrui , He Jinpeng , Wei Wenjun , Pei Hailong , Zhou Guangming , Wang Jufang , Wani Altaf A. , Zhu Qianzheng 
Published: August 2018

Abstract
MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that alter protein expression and regulate multiple intracellular processes including cellular stress response. We previously uncovered several novel miRNAs, whose expressions are induced by X-rays irradiation in HeLa cells, using a miRNA array. Here, we examined the function of miR-5094 during cellular radiation response. With software predictions and confirmatory experiments, we identified the signal transduction and activator of transcription 5b (STAT5b), a known regulator of proliferation and survival, as a target of miR-5094. The study also showed that both miR-5094 induction by X-rays irradiation and miR-5094 mimics transfection decreased STAT5b expression, down-regulated STAT5b downstream genes, and consequently, reduced the cell survival and cell viability. Knockdown of miR-5094 by miRNA inhibitor after radiation partially reversed these suppressive effects. As STAT5b plays an important role in lymphocyte proliferation, we further confirmed the proliferation inhibitory effects of miR-5094/STAT5b pathway on Jurkat cells and human peripheral blood CD4+ T cells during cell radiation response. In conclusion, our study provided the first evidence that radiation induces upregulation of miR-5094, which in turn inhibits cell proliferation via targeting STAT5b.
Citation Format: Nan Ding, Junrui Hua, Jinpeng He, Wenjun Wei, Hailong Pei, Guangming Zhou, Jufang Wang, Altaf A. Wani, Qianzheng Zhu. Radiation-induced miR-5094 expression inhibits cell proliferation by targeting STAT5b [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 4414.
Abstract 4415: Characterization of tumor-derived exosomes in BRCA-associated breast tumors
Authors: Shin Vivian Y. , Siu Man-Ting , Cheuk Isabella , Kwong Ava 
Published: August 2018

Abstract
Background: BRCA-mutated tumors are usually with higher grade than sporadic tumors and the biology is poorly understood. Exosomes are small membrane-derived vesicles that function to mediate cell-cell communication via the transfer of tumor-promoting microRNAs (miRNAs), RNAs and proteins. Interestingly, different spectrum of miRNAs is released by cancer cells to promote tumor growth and metastasis in breast cancer. However, the selectivity of miRNA released from tumor-derived exosomes and its relevance in cancer treatment has not been widely studied. Hence, this study is sought to characterize the role of exosomal-miRNA (exo-miR) for the development of BRCA-associated tumors. Methods: Plasma samples from patients with BRCA-positive and non-BRCA carriers were recruited and selected from the Hong Kong Hereditary Breast Cancer Family Registry. By using miRCURY LNA array, the exosomal-miRNA expressions in plasma of patient with BRCA-positive (n=4) and non-carriers (n=4), as well as healthy controls (n=4) were profiled. Selected miRNAs were further validated in pre- and post-operative plasma and paired primary tissues (n=40) using real-time RT-PCR. Functional study of miRNA was also carried out in the cell lines. Results: LNA array data showed that differential expressed BRCA-associated exo-miRNAs were identified. Upregulated miRs (miR-106a, miR-20a, miR-23a, miR-451 and miR-486) were validated in BRCA-positive, BRCA-negative and healthy controls by real-time RT-PCR. In addition, the expression levels of miR-106a, miR-451 and miR-486 were significantly lower in post-operative plasma of BRCA-carriers than non-carriers. Importantly, the expression of miR-451 was reduced after tumor resection in BRCA mutation carriers. In parallel, high expression of exo-miR-106a, miR-20a, miR-23a, miR-451 and miR-486 were also seen in breast cancer cell lines (MB-231 and MB-468) relative to normal breast cells (MCF-10A). We found that cells transfected with miR-451 inhibitor significantly reduce cell proliferation. Conclusions: These preliminary results reveal differential exo-miRNA profiles between BRCA carriers and non-carriers with breast cancer, and identify potential targets of dysregulated miRNAs which is crucial in disease progression of BRCA-associated breast cancers.
Citation Format: Vivian Y. Shin, Man-Ting Siu, Isabella Cheuk, Ava Kwong. Characterization of tumor-derived exosomes in BRCA-associated breast tumors [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 4415.
Abstract 4424: Micro-RNA mediated deregulation of hHB-EGF in ovarian cancer
Authors: Rahman Md. Mustafizur , Sultana Razia , Iwamoto Ryo , Mekada Eisuke 
Published: August 2018

Abstract
Background: Aberrant expression of microRNAs (miRNAs) has been implicated in human carcinogenesis where they function as oncogenes or tumor suppressor genes. Overexpression of HB-EGF, member of the epidermal growth factor (EGF) family, plays pivotal role in ovarian carcinogenesis. However the molecular mechanisms underlying miRNA(s) mediated aberrant function of HB-EGF in ovarian carcinoma remain unresolved. Here, we investigated the miRNA(s) mediated deregulation of HB-EGF in human ovarian carcinogenesis.
Methods: Web-based bioinformatics algorithms were used to identify candidate miRNAs with putative binding sites on target hHB-EGF mRNA. Expression of miRNAs and mRNA were checked by real-time PCR whereas protein expression was investigated by western blotting assay. Luciferase reporter assay was carried out to examine miR-27a target on 3´UTR of hHB-EGF mRNA. Changes in the oncogenic effects of HB-EGF were studied after gain/loss -of-function of the miR-27a using soft agar colony formation assay and 3D collagen culture. In vivo tumor growth potential of miR-27a was measured in BALB/c nude mice.
Results: By using web-based bioinformatics algorithms 11 miRNAs ((miR-27a/b, -29a/b/c, -96, -128, -132, -182,-194, -212) having putative binding sites on the 3′UTR of hHB-EGF mRNA have been selected for further analysis. Among the putative candidates miR-27a showed maximum reciprocal expression with hHB-EGF and thus we selected miR-27a as promising candidate for hHB-EGF regulation. Overexpression of miR-27a significantly inhibited the hHB-EGF expression in SKOV3 cells by almost 50% and miR-27a inhibitors (anti-miR-27a) upregulated the expression of endogenous hHB-EGF mRNA whereas miR-27a overexpression decreased hHB-EGF protein level in MCAS cells suggesting that miR-27a modulate endogenous hHB-EGF expression both at mRNA and protein level. Luciferase reporter assay revealed that miR-27a directly targets 3´UTR of hHB-EGF mRNA at the predicted site. Ectopic expression of miR-27a suppresses in-vitro growth of SKOV3 ovarian cancer cells. In addition, in-vivo tumorigenecity of SKOV3 cells was also inhibited by miR-27a treatment.
Conclusion: The current study has identified novel miR-27a that negatively regulates hHB-EGF expression by directly targeting 3`UTR of its mRNA. This miR-27a might act as oncosupressor in human epithelial ovarian cancer.
Citation Format: Md. Mustafizur Rahman, Razia Sultana, Ryo Iwamoto, Eisuke Mekada. Micro-RNA mediated deregulation of hHB-EGF in ovarian 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 4424.
Abstract 4427: Preparation and mechanism of polyethyleneimine coated miRNA let-7a microspheres
Authors: Lai Honglin , An Weixiao , Zhang Yangyang , Lin Xiukun , Cao Shousong 
Published: August 2018

Abstract
Recent evidence demonstrates that microRNAs (miRNAs) are associated with cancer development and have the potential to be used as anticancer agents. However, the application of miRNAs as clinical cancer drugs has been limited due to their unstability at room temperature. Moreover, miRNAs are negatively charged and excluded by cytomembrane, which has the same polarity. Therefore, miRNAs are difficult to enter cancer cells to exhibit their anticancer effects. In order to solve the problem, we changed the polarity of miRNA let-7a, a member of the second identified miRNA let-7 families, by coating with a bioavailable polymer, polyethylenimine (PEI) using nanotechnology, to alter the charge of miRNA let-7a for positive charge so easily connecting with the anionic residues of cancer cell surfaces. Therefore, miRNA let-7a could easily entered cells through endocytosis. In addition, we performed formaldehyde denaturing SDS-PAGE analysis to determine the stability of miRNA let-7a, and we found the stability of miRNA let-7a has been significantly increased due to microspheres formation. MiRNA let-7a microspheres have showed potent cytotoxicity against a variety of cancer cells including HCT-116, A875, A549, and 4T1 cells with the IC50 as 31.77, 54.34, 44.35, 43.18 pmol/l, respectively by CCK-8 kit analysis. We also found that miRNA let-7a microspheres are able to induce cell apoptosis by promoting the expression of apoptosis-related genes Caspase 3, Caspase 9 and PARP in HCT-116 and A875 cells. Our findings may provide that miRNA let-7a microspheres may be developed as a novel anticancer agents in cancer therapy.
Citation Format: Honglin Lai, Weixiao An, Yangyang Zhang, Xiukun Lin, Shousong Cao. Preparation and mechanism of polyethyleneimine coated miRNA let-7a microspheres [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 4427.
Abstract 4440: Differential regulation of p63 isoforms by alternative polyadenylation
Authors: Mohibi Shakur , Zhang Jin , Chen Xinbin 
Published: August 2018

Abstract
p63, a transcription factor belonging to the p53 family, plays vital roles in epidermal development and tumorigenesis. p63 expresses from two different promoters generating two classes of proteins, TAp63 and ΔNp63 that differ in their N-terminus. Moreover, alternative splicing of the TA and ΔN isoforms in the C-terminus creates additional isoforms (α-ϵ); thus generating five TA and five ΔN p63 isoforms. The factors that give rise to this repertoire of p63 isoforms are not very well understood. Alternative polyadenylation (APA) can generate multiple isoforms of a gene with alternative 3' ends based on the polyadenylation site selection during cleavage and polyadenylation of mRNA. APA can give rise to isoforms that differ in the coding region (CDS APA) or that have varying lengths of 3' UTR (3' UTR APA). Recently, PABPN1 protein that binds the 3' poly(A) tail of mRNAs has emerged as a key regulator of APA. Here, we show that PABPN1 differentially regulates p63α and p63γ isoforms by alternative polyadenylation. Specifically, knockdown of PABPN1 increases the levels of p63γ mRNA as well as protein by regulating CDS APA of p63 gene. Moreover, knockdown of PABPN1 also generates p63α mRNAs with varying 3' UTR lengths. Although the mRNA levels of p63α remain unchanged upon PABPN1 KD, p63α protein is significantly decreased, suggesting that PABPN1 also regulates p63α protein translation. Interestingly, we also show that PABPN1 is a p63α target and that p63 transcriptionally regulates PABPN1 by binding to its promoter forming a negative feedback loop. Taken together, our study identifies PABPN1 as a novel regulator of various p63 isoforms by APA and that p63 in turn regulates PABPN1 transcriptionally.
Citation Format: Shakur Mohibi, Jin Zhang, Xinbin Chen. Differential regulation of p63 isoforms by alternative polyadenylation [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 4440.