bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-365: Microscopic imaging for understanding gold nanorods-protein interactions in inhibiting cancer cell migration
Authors: Wu Yue , Ali Moustafa R. , Fang Ning , El-Sayed Mostafa A. 
Published: August 2018

Abstract
Metastasis is the primary cause of cancer-related deaths. Current clinical treatments for anti-metastasis, however, are not effective. Gold nanorods (AuNRs), which are safe within biological systems, were recently discovered to inhibit cancer cell migration and prevent metastasis. However, the mechanism of how AuNRs inhibit cancer cell migration remains largely unexplored. The migration of cancer cells from one site to another requires dramatic remodeling of cytoskeleton proteins. Our recent studies have shown a great impact of AuNRs treatment on proteins that regulate the cytoskeleton. However, the interaction of AuNRs and the cytoskeletal structures are not well studied due to the lack of advanced microscopic technologies at single nanoparticle-single protein level. Herein, we used cutting-edge imaging techniques to enable the study of the direct correlation between cytoskeleton filaments (microtubule) and AuNRs . Differential interference contrast (DIC) (for imaging AuNRs) and the stochastic optical reconstruction microscopy (STORM) (for imaging proteins) were combined to resolve the interaction of how AuNRs interact with the cytoskeleton filaments, disrupt the cytoskeleton structures, including microtubule and therefore inhibit cell migration. In conclusion, we are able to visualize the interaction of AuNRs with cytoskeleton filaments at nanometer resolution with their accurate intracellular location, which is beneficial for the future studies of nanoparticle-cell interactions.
Citation Format: Yue Wu, Moustafa R. Ali, Ning Fang, Mostafa A. El-Sayed. Microscopic imaging for understanding gold nanorods-protein interactions in inhibiting cancer cell migration [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 LB-365.
Abstract LB-376: Clinico-genomic analysis of temozolomide-induced hypermutation in both molecular subtypes of IDH-mutant glioma
Authors: Grimmer Matthew R. 
Published: August 2018

Abstract
Hypermutated gliomas arising from treatment with alkylating agents, such as temozolomide (TMZ), are genetically distinct, recurrent tumors about which very little is known. Here, we have identified common and subtype-specific patterns in the tumor evolution of IDH-mutant, low-grade astrocytoma (1p/19q-intact) and oligodendroglioma (1p/19q-codeleted) from 57 glioma patients. Hypermutation involved unanimous defects in mismatch repair in both subtypes, with unique mismatch repair alterations differentiating hypermutation events in serial recurrences. Hypermutation was associated with malignant progression in astrocytoma, and can differentiate high-grade regions from low-grade regions within the same tumor. Hypermutated oligodendroglioma tumors associated with newly-arising p53 mutations and mirrored the early branching evolution of astrocytoma tumors. Results from this longitudinal clinical-genomic study suggest prominent roles for MMR and p53 in the establishment and maintenance of hypermutation. The evolution of TMZ-related tumor antigens across serial tumor recurrences will be presented.
Citation Format: Matthew R. Grimmer. Clinico-genomic analysis of temozolomide-induced hypermutation in both molecular subtypes of IDH-mutant glioma [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 LB-376.
Abstract LB-380: TMB calling in absence of matched normal: Learning germline behavior
Authors: Tian Yiqing , Jones Wendell , Mola Natalie , Weigman Victor J. 
Published: August 2018

Abstract
In most standard cases, mutational burden is derived from samples where mutational calling is performed in tumor and matched normal specimens. While this is ideal to get a true sense of tumor-derived mutations, it creates limitations due to cost of extra sequencing or in many trials, unavailable for genomic profiling. Without this normal material, there are increased difficulties of eliciting the accurate somatic mutation calls away from natural variation. This is even further complicated by the fact that different tumor types have different spectra of mutations so a method built on an individual indication have risks of overfitting. We present here the results of our investigations of machine learning to build reliable germline variant estimates appropriate for use in calculating burden. In this draft, we examine two tumor mutation classification methods based on our latest TMB tool: random forest and neural network across multiple indications in TCGA. We compare calls made by these methods against burden scores that we have generated from our own paired tumor/normal method (sister submission) to determine accuracy. Using sampled tumor results from each indication, different models were built across both random forest and neural networks, showing accuracy in some indications, up to 98%. Looking to work to create and indication-independent classifier, validation results show we can reach an average of 89% accuracy where training is built across all indications. In all cases, cross validation was performed to prove the consistency of the classification method and test the algorithm on our latest tumor only data set against what was generated from paired results.
Citation Format: Yiqing Tian, Wendell Jones, Natalie Mola, Victor J. Weigman. TMB calling in absence of matched normal: Learning germline behavior [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 LB-380.
Abstract LB-390: A transfer RNA derived small RNA affects translation in rapidly dividing cells and a target for hepatocellular carcinoma
Authors: Kim Hak Kyun , Fuchs Gabriele , Wang Shengchun , Wei Wei , Zhang Yue , Park Hyesuk , Roy-Chaudhuri Biswajoy , Li Pan , Xu Jianpeng , Chu Kirk , Zhang Feijie , Chua Mei-sze , So Samuel , Zhang Cliff , Sarnow Peter , Kay Mark A. 
Published: August 2018

Abstract
There are tens of thousands of different transfer RNA-derived small RNAs (tsRNAs) of 18-40 nucleotides in length in mammalian cells. In recent years there is accumulating evidence suggesting that these RNAs can play different yet important roles in gene regulations. Nevertheless, in most cases, the biological roles of these RNAs have yet to be defined. Using a variety of locked nucleic acid/antisense oligonucleotide (LNA/ASO)-mediated strategies, we found that inhibition of one specific 3'tsRNA, induces apoptosis in rapidly dividing cells. Inhibition of the tsRNA but not the mature tRNA reduced the translation of ribosomal protein S28 (RPS28) and S15 (RPS15) mRNAs and led to a block in pre-18S ribosomal RNA processing, and ultimately a decrease in the number of 40S ribosomal subunits. Using a modified ChIRP method, we found that the tsRNA binds to ribosomal protein S28 mRNA and by genetic complementation analyses established the binding sites contained within the mRNAs. Furthermore, we established that tsRNA binds to duplexed target sites in RPS28 and RPS15 mRNAs and enhances their translation by perhaps helping to unfold their secondary structures. The systemic delivery of a specific anti-tsRNA oligonucleotides into mice (the tsRNA sequence is the same in mouse and humans) did not cause liver injury in normal mice but induced apoptosis and a significant growth retardation of patient-derived orthotopic hepatocellular carcinomas surgically implanted into mouse livers. Our result establishes a newly defined post-transcriptional mechanism of gene regulation and provides a novel target for cancer therapeutics.
Citation Format: Hak Kyun Kim, Gabriele Fuchs, Shengchun Wang, Wei Wei, Yue Zhang, Hyesuk Park, Biswajoy Roy-Chaudhuri, Pan Li, Jianpeng Xu, Kirk Chu, Feijie Zhang, Mei-sze Chua, Samuel So, Cliff Zhang, Peter Sarnow, Mark A. Kay. A transfer RNA derived small RNA affects translation in rapidly dividing cells and a target for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-390.
Abstract LB-393: LINC01137 functions as a ceRNA promoting SMAD3 signaling and ESCC metastasis
Authors: Shao Mingming , Chu Jiahui , Cui Qionghua , Peng Linna , Luo Yingying , Chang Jiang , Tan Wen , Wu Chen , Lin Dongxin 
Published: August 2018

Abstract
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading cause of cancer-related death in China and some other parts of the world. Studies have shown that certain long non-coding RNAs (lncRNAs) are involved in cancer development and progression. In this study, we sought to identify lncRNAs that are associated with metastasis of ESCC and to explore their functions and therapeutic implications.
METHODS: We performed RNA sequencing and analyzed the association of lncRNAs with ESCC survial time. The significantly associated lncRNAs that were overexpressed in ESCC were selected for further study. Knockdown or overexpression of interest lncRNAs were performed to investigate their effects on ESCC cell invasion and metastasis in vitro and in vivo in mice xengraft models. Biochemical assays such as RNAi, RNA immunoprecipitation, RNA pulldown and chromatin immunoprecipitation assays were used to examine the interactions among lncRNAs, mRNAs and microRNAs and between proteins and DNA. Patient survival time differentiated by RNA expression levels was estimated by Kaplan-Meier plotting and hazard ratios for death were calculated by Cox models.
RESULTS: RNA sequencing identified 9 overexpressed lncRNAs were associated with ESCC survival. Among these lncRNAs, LINC01137 had the strongest effects on invasion and metastasis of ESCC cell lines in vitro and in vivo in mice. We found that ESCCwith high expression of LINC01137 had significantly more lymph node metastases compared with ESCC with low expression of LINC01137. Functional analyses demonstrated that LINC01137 may compete with HOXA1 mRNA for miR-608 binding. Higher expression level of LINC01137 in cells may prevent miR-608 from inhibiting HOXA1 translation. We found that HOXA1 is a transcription activator of SMAD2/3 and knockdown of LINC01137 substantilly reduced the SMAD3 signaling. Treatment of ESCC cells overexpressing LINC01137 with Halofuginone, a plant derivative that can inhibit SMAD3 phosphorylation, significantly reduced the abilities of migration and invasion.
CONCLUSION: These results suggest that LINC01137 might function as a ceRNA competing with miR-608 for suppressing HOXA1 expression, which promotes SMAD3 signaling to enhance metastasis of ESCC cells.
Citation Format: Mingming Shao, Jiahui Chu, Qionghua Cui, Linna Peng, Yingying Luo, Jiang Chang, Wen Tan, Chen Wu, Dongxin Lin. LINC01137 functions as a ceRNA promoting SMAD3 signaling and ESCC metastasis [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 LB-393.
Abstract SY19-02: Novel mechanisms of acquired resistance to selective CDK4/6 inhibition
Authors: Shapiro Geoffrey I. 
Published: August 2018

Abstract
CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor (ER)-positive breast cancer, so that understanding mechanisms of resistance is a pressing issue. We have identified identified increased CDK6 expression as a key determinant of acquired resistance after exposure to palbociclib in ER-positive breast cancer cells. Increased CDK6 in resistant cells is dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal miR-432-5p expression mediated transfer of the resistance phenotype between neighboring cell populations, causing previously sensitive cells to acquire CDK4/6 inhibitor resistance. We confirmed these data in pretreatment and postprogression biopsies from a parotid cancer patient who had responded to ribociclib, demonstrating that this resistance mechanism is clinically relevant. Additionally, this CDK4/6 inhibitor resistance phenotype can be reversed in vitro and in vivo by a prolonged drug holiday, which restored drug sensitivity. CDK4 is also emerging as a target in KRAS-mutant non-small cell lung cancer (NSCLC). We have demonstrated that KRAS-mutant NSCLC cell lines are initially sensitive to palbociclib, but readily acquire resistance associated with increased expression of CDK6, D-cyclins, and cyclin E. Resistant cells also demonstrated increased ERK1/2 activity and sensitivity to MEK and ERK inhibitors. Moreover, MEK inhibition reduced the expression and activity of cell cycle proteins mediating palbociclib resistance. In resistant cells, ERK activated mTOR, driven in part by upstream FGFR1 signaling resulting from the extracellular secretion of FGF ligands. A genetically engineered mouse model of KRAS-mutant NSCLC initially sensitive to palbociclib similarly developed acquired resistance with increased expression of cell cycle mediators, ERK1/2 and FGFR1. In this model, resistance was delayed with combined palbociclib and MEK inhibitor treatment. These findings implicate an FGFR1-MAP kinase-mTOR pathway resulting in increased expression of D-cyclins and CDK6 that confers palbociclib resistance, and indicate that CDK4/6 inhibition acts to promote MAP kinase dependence.
Citation Format: Geoffrey I. Shapiro. Novel mechanisms of acquired resistance to selective CDK4/6 inhibition [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 SY19-02.
Abstract SY38-01: Inflammation-induced neutrophil extracellular traps (NETs) awaken dormant cancer in the lung microenvironment
Authors: Egeblad Mikala 
Published: August 2018

Abstract
To elucidate mechanisms of cancer metastasis and recurrence from minimal residual disease, we use intravital imaging allowing for long-term visualization of cancer cells and surrounding host cells in living mice. Using intravital imaging, we found that neutrophils, the most abundant type of leukocytes in blood, form neutrophil extracellular traps (NETs) near disseminated cancer cells in the lung of mice during experimental inflammation. NETs are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes in response to, e.g., infections. However, we found that metastatic breast cancer cells themselves can induce neutrophils to form metastasis-supporting NETs, in the absence of infection. We also found NETs in clinical samples of metastatic, triple-negative human breast cancer. Using mouse models, we determined that NETs promote metastasis by facilitating proteolytic extracellular matrix remodeling. Pharmacologic inhibition of NET formation or digestion of NETs with DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs is an important host-mediated mechanism of promoting metastasis and a potential therapeutic target.
Citation Format: Mikala Egeblad. Inflammation-induced neutrophil extracellular traps (NETs) awaken dormant cancer in the lung microenvironment [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 SY38-01.
Abstract A07: DNA methylation predicts response of triple-negative breast cancer to all-trans retinoic acid treatment
Authors: Coyle Krysta M. , Dean Cheryl A. , Vidovic Dejan , Weaver Ian , Giacomantonio Carman , Helyer Lucy , Marcato Paola 
Published: August 2018

Abstract
We have identified a novel, epigenetic-based strategy to identify breast cancer patients who will benefit from an existing anticancer agent, all-trans retinoic acid (atRA). Triple-negative breast cancer (TNBC) is among the most aggressive breast cancers and lacks targeted therapies. TNBCs are a heterogeneous group of breast cancers with a wide range of gene expression profiles and drug sensitivities. Profiling these differences will lead to the development of more effective treatment options for TNBC. We hypothesize that atRA can be an effective therapy for a subset of TNBC patients. To test our hypothesis, we profiled the response of 12 TNBC cell lines to atRA using in vivo tumor growth assays. We found that atRA treatment had a range of effects on the tumor growth of TNBC cell lines: significantly decreasing tumor growth in HCC70, SUM149, and HCC1937, while increasing the growth of MDA-MB-231, MDA-MB-436, and Du4475 tumors. Gene expression and methylation analysis of these 12 cell lines revealed subtype-specific expression of atRA-inducible genes due to silencing by DNA methylation, e.g., of the atRA-inducible tumor-suppressor gene RARRES1. RARRES1 is silenced by methylation in cell lines where atRA promotes tumor growth, but is hypomethylated and expressed in cells that can be effectively treated with atRA. Use of the distinct gene expression and methylation profiles allowed us to accurately predict the response of 4 patient-derived xenografts (PDXs) to RA treatment. Continued classification of TNBCs by gene expression and DNA methylation can predict the response of patient tumors to RA treatment, thus identifying a novel targeted therapy strategy for TNBCs.
Citation Format: Krysta M. Coyle, Cheryl A. Dean, Dejan Vidovic, Ian Weaver, Carman Giacomantonio, Lucy Helyer, Paola Marcato. DNA methylation predicts response of triple-negative breast cancer to all-trans retinoic acid treatment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A07.
Abstract A15: DNA damage response-targeted molecules for breast cancer therapy
Authors: Valenea Alfredo , Grindrod Scott , Jung Mira 
Published: August 2018

Abstract
Breast cancer genes 1 and 2 (BRACA1 and BRACA2) are known to be linked to breast cancer risk. BRCA1 is an ATM substrate and plays critical roles in the DNA damage response (DDR) and maintenance of genomic stability. Furthermore, recent studies have shown that the aberrant expression of DNA damage repair transducer, ataxia-telangiectasia mutated (ATM), is associated with breast cancers. To develop target-specific drugs, we rationally designed a dual-function small molecule, SP-1-303, by conferring ATM activation and HDAC inhibition activity. The compound was screened against a panel of Class I and Class II HDAC enzymes in vitro and identified as a pan-HDAC inhibitor at an IC50 of 120 nM. Western analysis revealed that SP-1-303 increased acetylated histone H3/H4, α-tubulin, and ATM activation (p-ATM/S1987). Testing two ER-positive BC cell lines (MCF7 and T-47D), two triple-negative breast cancer (TNBC) cell lines (MDA-MB-231 and HCC 1937), and one normal breast epithelial cell line as a control (MCF10A), the effect of SP-1-303 on cell growth was examined by cytotoxicity assays. SP-1-303 demonstrated cytotoxicity (IC50) of ER-positive BC cells in a range of 0.2-0.3 μM, while the values for TNBC cells are in a range of 1-3 μM and 12 μM for normal breast epithelial cells, respectively. Furthermore, proteomic analysis of MCF7 cells following SP-1-303 treatment identified differential effects on expression of various DDR molecules and chromatin regulators, including ATM, BRCA1, TP53BP1, NBN, histones, and chromatin remodelers. Taken together, SP-1-303 shows specificity for ER-positive breast cancers, potentially by modulating the DDR signaling pathway.
Citation Format: Alfredo Valenea, Scott Grindrod, Mira Jung. DNA damage response-targeted molecules for breast cancer therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A15.
Abstract A24: SAS1B protein: Determining whether ASTL or SAS1B has a role in tumor progression
Authors: Khokhar Zunair Shakeel , Kim Alexander J. , Pires Eusebio , D’Souza Ryan 
Published: August 2018

Abstract
The matrix metalloproteinase- Sperm Acrosomal SLLP1 Binding (SAS1B) is an ideal molecular and cellular candidate for both female contraception and for cancer therapies. SAS1B translation is restricted among adult tissues to the ovary and oocytes, and SAS1B first appears in oocytes of follicles at the primary-secondary transition and also in tumors of varied types and stages. Research conducted using SAS1B antibodies suggested that the protein is localized at the cell membrane of cancer cells and can get internalized in a classical endocytosis assay and can be killed using an immunotoxin linked onto antibodies. The current study aims at deciphering whether the ASTL gene or the SAS1B protein is important for tumor progression, invasion and metastasis through cell biology and molecular biology tools and ensuring tumor cell killing properties via an ADC mediated killing using biochemistry and molecular biology tools. PCR, immunohistochemistry, Immunofluorescence, and Western Blots revealed that a non cancerous breast cell line MCF10A5E is SAS1B null and can be used to study cancer like properties once stably transfected with the SAS1B construct. Previous work in the lab indicated that an SAS1B-ADC strategy is a viable immunotherapy that could benefit patients who have failed to respond to chemotherapy, if indeed SAS1B plays a role in cancer development and progression. The outcomes of a SAS1B-ADC in a breast cancer model will be presented.
Citation Format: Zunair Shakeel Khokhar, Alexander J. Kim, Eusebio Pires, Ryan D’Souza. SAS1B protein: Determining whether ASTL or SAS1B has a role in tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A24.