bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4326: The chromatin context and consequence of cisplatin-adduct DNA damage
Authors: Gallon John , Loomis Erick , Martin Nicholas , Flanagan James , Brown Robert 
Published: August 2018

Abstract
Improvements in survival rates for ovarian cancer lag behind those of other cancers. The combination of paclitaxel and carboplatin, along with debulking surgery, form the primary mode of treatment, however, the majority of patients eventually develop resistance. Epigenetic mechanisms have been implicated in the emergence of drug resistance, with platinum based therapies shown to induce DNA methylation changes at relapse which are associated with overall survival. Using a next generation sequencing approach, including a novel NGS method to map platinum adducts, we sought to investigate the association between platinum-DNA adduct formation and changes to chromatin conformation in the emergence of resistance to platinum therapy. We found chromatin conformation changes at the transcription start sites (TSS) of genes differentially expressed between platinum sensitive and resistant cell lines (p&lt;0.05, n=3 pairs). Furthermore, we found non-TSS associated chromatin conformation changes which distinguish sensitive from resistant lines, and occur primarily in the direction of reduced accessibility in resistant lines (FDR &lt;0.05, log2FC &gt;±1.5). Finally, we found that 2kb windows enriched for platinum-DNA adducts are significantly more accessible than an equal number of random windows on the same chromosome (p&lt;0.05, 1000 permutations). Taken together, these data suggest that platinum treatment may induce epigenetic changes, which reduce chromatin accessibility, rendering cells less susceptible to the formation of platinum-DNA adducts in subsequent treatments, resulting in cells becoming less sensitive to the drug.
Citation Format: John Gallon, Erick Loomis, Nicholas Martin, James Flanagan, Robert Brown. The chromatin context and consequence of cisplatin-adduct DNA damage [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 4326.
Abstract 4328: hTERT protein expression, hTERT methylation and HPV infection in uterine cervical cancer
Authors: Moreno-Acosta Pablo , Molano Mónica , Morales Nicolas , Romero-Rojas Alfredo , Gamboa Oscar , Acosta Jinneth , Alvarez Raynner , Magné Nicolas , Muñoz Nubia 
Published: August 2018

Abstract
The analysis of expression of the hTERT protein, the methylation status of the hTERT gene as the type of HPV infection, will contribute to deepen the role played by HPV infection in the expression and methylation of hTERT. The study included a group of one hundred fifty-five samples of women with squamous cell carcinomas of the uterine cervix in stage FIGO IIB-IIIB treated at the National Cancer Institute in Bogotá, Colombia. The expression of the hTERT protein was detected by immunohistochemistry both at the nuclear level and at the cytoplasmic level. In 79.7% of the cases, the protein was expressed at the nuclear level and 78% at the cytoplasmic level. HPV16, the most frequent viral type found, was detected by means of a GP5+/GP6+ mediated PCR- RLB in 84.4% and in 82.2% of the cases that expressed hTERT at the nuclear level and at the cytoplasmic level, respectively; with respect to HPV species, both at the nuclear level and at the cytoplasmic level, the species most frequently found was the alpha 9 species (HPVs 16, 31, 35, 52.58) followed by alpha 7 (HPVs 18, 45.59) and alpha 6 (HPVs 56, 66). In the multiple correspondence analyzes, a close relationship was observed between the cytoplasmic expression as nuclear of hTERT and the alpha species 9. A distant relationship was also observed between the expression of the protein and methylation, as well as between the non-methylation and the alpha 7 family of HPV; likewise, a distant relationship was observed between the non-methylation of hTERT and the alpha 9 species. The analyzes carried out show a possible relationship between the expression of the hTERT protein and the alpha 9 HPV species.
Citation Format: Pablo Moreno-Acosta, Mónica Molano, Nicolas Morales, Alfredo Romero-Rojas, Oscar Gamboa, Jinneth Acosta, Raynner Alvarez, Nicolas Magné, Nubia Muñoz. hTERT protein expression, hTERT methylation and HPV infection in uterine cervical 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 4328.
Abstract 4331: High-throughput whole-genome sequencing of formalin fixed, paraffin-embedded tissues from colorectal cancer patients
Authors: Kubit Matthew , Wood-Bouwens Christina , Grimes Sue , Bell John , Shin GiWon , Lau Billy , Miller Mickey , Day Kenneth , Escobar Helaman , Ji Hanlee , Nadauld Lincoln , Hummelen Paul Van 
Published: August 2018

Abstract
Formalin-fixed, paraffin-embedded (FFPE) storage is a universally-adopted, cost-effective and long-term solution for tissue storage. Given the abundance of FFPE clinical samples, they provide a good source of tissue for genome sequencing studies. However, the extraction of nucleic acids from FFPE tissues yield highly fragmented DNA of variable quality. The poor quality and low yield make it difficult to generate adequate sequencing libraries for genomic studies.
For a population cancer genome study, we optimized a procedure for whole-genome sequencing on FFPE tumor and normal tissue of colorectal cancer patients. This pilot study aimed to first identify changes in DNA copy number using low-pass sequencing, with the additional goal of later adding structural variant and gene fusion detection and single nucleotide variant analysis with deeper sequencing. We processed, sequenced and analyzed 193 patients. These FFPE samples had varying storage characteristics. We optimized the initial extraction quality thresholds, DNA extraction and library preparation to generate high quality sequencing data.
We identified an initial sample quality and library threshold to hold the best correlation for sequencing quality. Optimal yield and DNA size from extracted FFPE was achieved by using Promega's LEV DNA FFPE Extraction Kit. Library prep optimization involved using mechanical shearing of DNA to increase overall library size for structural variant detection as well as using unique dual index adapters to identify index swapping artifacts during sequencing. An additional cleanup was also performed post-fragmentation to increase overall library size. Overall, we successfully developed a robust protocol for conducting whole genome sequencing on FFPE tumor samples.
Citation Format: Matthew Kubit, Christina Wood-Bouwens, Sue Grimes, John Bell, GiWon Shin, Billy Lau, Mickey Miller, Kenneth Day, Helaman Escobar, Hanlee Ji, Lincoln Nadauld, Paul Van Hummelen. High-throughput whole-genome sequencing of formalin fixed, paraffin-embedded tissues from colorectal cancer patients [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 4331.
Abstract 4334: Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal cancer
Authors: Xia Li C. , Bell John M. , Wood-Bouwens Christina , King Daniel A. , Shin GiWon , Greer Stephanie , Connolly Ian D. , Gephart Melanie H. , Ji Hanlee P. 
Published: August 2018

Abstract
Little is known about the genomic features of brain metastases from colorectal cancer (CRC) and the contributing genetic factors. We conducted an analysis of large-scale structural aberrations, including chromosome aneuploidies, with a method called linked-read whole genome sequencing and a new somatic rearrangement detection software tool (ZoomX) to better understand the genomic architecture of brain metastases from CRC. We resolved on average 145 distal inter- and intra-chromosomal somatic junctions per sample with their exact haplotype information and basepair level breakpoints. In addition, we used a new haplotyping method based on these imbalances to generate cancer chromosome haplotypes of up to 146 Mbp long. We identified extensive chromosomal-level instability (CIN) in these cancer genomes, with an average of 90 large-scale copy number aberrations per sample in sizes ranging from hundreds of Kbp to hundreds of Mbp. A substantial fraction of CIN is likely attributable to earlier chromothripsis events. For example, we identified multiple chromothripsis events disrupting the loci of known cancer genes such as TP53, an essential colon cancer driver. We identified novel rearrangements including an oncogenic gene fusion; e.g. SET/DPP10 among these metastatic samples. A majority of chromosome arms demonstrated an allelic imbalance across all of the samples. In summary, the analysis revealed pervasive chromosome-level genome instability as a potential contributor to devastating brain invasion by CRC. It also demonstrated the advantages of linked-read whole genome sequencing. This approach is cost-effective and represents a high-resolution tool to assess genome-wide rearrangements and to generate megabase-scale haplotypes.
Citation Format: Li C. Xia, John M. Bell, Christina Wood-Bouwens, Daniel A. King, GiWon Shin, Stephanie Greer, Ian D. Connolly, Melanie H. Gephart, Hanlee P. Ji. Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal 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 4334.
Abstract 4352: High caveolin-1 expression in African American women with early-stage triple-negative breast cancer
Authors: Baumbach-Reardon Lisa L. , Getz Julie , Ahearn Mary E. , Carpten John , Pegram Mark 
Published: August 2018

Abstract
In the U.S., the incidence rates of breast cancer (BC) among Caucasian (CA) women are lower than those of African American (AA); however, AA women have a significantly higher mortality rate. It is imperative that we continue to investigate the underlying molecular biology that may contribute to the cause of health disparities between AA and CA with TNBC. In this study, gene expression profiling, using the Almac BC DSA Research Tool, was performed on archived FFPE samples, obtained from CA and AA women diagnosed with early-stage (Node 0) TNBC. Unsupervised hierarchical clustering revealed a pattern of differential gene expression in the AA cohort compared to CA. Using a subtyping Tool for TNBC, we found a distinct distribution pattern of TNBC molecular subtypes in the AA cohort, which was very different than the CA cohort: basal-like (14%), immunomodulatory (43%) and mesenchymal (43%). Gene expression analyses, comparing the AA and CA cohort (fold change &gt; 2.0, p-value &lt;.05), resulted in 190 differentially expressed genes (DEG). Pathway enrichment analysis conducted in MetaCore GeneGo revealed that the DEGs were over-represented in cytoskeletal remodeling, cell adhesion, tight junctions, and immune response in the AA TNBC cohort. Furthermore, several genes in the Wnt/β-catenin pathways were overexpressed in the top 10 enrichment pathways. We validated our results using RT-qPCR and identified Caveolin-1 (CAV1) as being significantly expressed in the AA-TNBC cohort (p-value 1.22 x 10-05). An independent cohort of FFPE samples, from AA and CA women with early stage TNBC, was used to create a tissue microarray (TMA). Immunohistochemistry results showed no difference in subcelluar localization of Cav1 between the AA and CA cohorts; however, the AA cohort had significantly higher levels of Cav1 staining (p-value 0.04). Additionally, using RT-qPCR, we demonstrated that CAV1 mRNA was significantly higher in the AA TNBC cohort (p-value 0.48). Furthermore, endogenous Cav1 was shown to be highly expressed in a cell line panel of TNBC, in particular, those of the mesenchymal and basal-like molecular subtypes. Finally, using siRNA, we demonstrated that CAV1 silencing resulted in a significant decrease in cell proliferation for each of the TNBC cell lines while it showed no effect on the luminal ER+ cell lines. Our combined study results suggest that CAV1 overexpression may be a biologic contributor to the observed health disparity between AA women and CA diagnosed with early-stage TNBC.
Citation Format: Lisa L. Baumbach-Reardon, Julie Getz, Mary E. Ahearn, John Carpten, Mark Pegram. High caveolin-1 expression in African American women with early-stage triple-negative 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 4352.
Abstract 4359: Several cancer types are associated with increased expression and activity of the ECT2 RhoGEF and decreased expression and activity of the DLC1 RhoGAP, leading to increased RhoA activity
Authors: Wang Dunrui , Qian Xiaolan , Durkin Marian E. , Papageorge Alexander G. , Lowy Douglas R. 
Published: August 2018

Abstract
RhoA, which is a member of the Ras family of small GTPases, whose proteins cycle between an active GTP-bound form and an inactive GDP-bound form, frequently has high activity in advanced cancer. The RhoA protein is activated by RhoGEFs, which catalyze replacement of bound-GDP with bound-GTP, and inactivated by RhoGAPs, which hydrolyze bound-GTP to bound-GDP. In this study, we have used the The Cancer Genome Atlas (TCGA) and the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to examine the relationship between a specific RhoGEF, ECT2, and a specific RhoGAP, DLC1, and experimentally tested the biological relevance of some key findings. Using the TCGA dabase, we have found increased expression of the ECT2 RhoGEF frequently occurs in synchrony with decreased expression of the DLC1 RhoGAP in several tumor types, including lung adenocarcinoma, lung squamous cell carcinoma, and hepatocellular cancer. In lung adenocarcinoma, the combination of high ECT2 expression and low DLC1 expression level is more common in poorly differentiated tumors than in well differentiated ones. Using other publicly available datasets from NCBI Gene Expression Omnibus (GEO), the expression DLC1 and ECT2 was found to be cell cycle related, with higher DLC1 being observed exclusively in the G0 phase, while ECT2 was higher during the cell cycle, relative to G0, and peaked in the G2/M phase. In CPTAC, phosphorylation of a specific ECT2 amino acid (S861) is correlated with a poor prognosis in breast cancer. Consistent with this observation, experimental mutation of ECT2 S861 to A861 results in an ECT2 gene with loss-of-function. Point mutation of ECT2 and DLC1 were found at overall frequencies of 1.7% and 4.7%, respectively, in the tumors of the TCGA database. These cancer-associated mutations occur along the entire length of the ECT2 and DLC1 proteins, rather than being located primarily in the Rho-GEF domain of ECT2 or the Rho-GAP domain of DLC1, and experimental analysis of a subset of these mutants indicates that most of the ECT2 mutants are gain-of-function, while most of the DLC1 mutants are loss-of-function. Our results imply that ECT2 and DLC1 frequently act in concert, but in opposite directions, in cancer to increase RhoA activity.
* Authors contributed equally to this abstract
Citation Format: Dunrui Wang, Xiaolan Qian, Marian E. Durkin, Alexander G. Papageorge, Douglas R. Lowy. Several cancer types are associated with increased expression and activity of the ECT2 RhoGEF and decreased expression and activity of the DLC1 RhoGAP, leading to increased RhoA activity [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 4359.
Abstract 4360: Altering the regulation of KRAS GTPase cycle via Src and SHP2 creates a potential therapeutic vulnerability for pancreatic cancer
Authors: Gebregiworgis Teklab , Marshall Christopher B. , Kano Yoshihito , Radulovich Nikolina , Tsao Ming-Sound , Ohh Michael , Ikura Mitsuhiko 
Published: August 2018

Abstract
More than 30% of all human cancers have Ras mutations and more than 95% of pancreatic cancers harbor KRAS mutations. However, therapeutically targeting cancers driven by oncogenic Ras mutations is still an ongoing investigation. KRas is a small GTPase found in either a GDP-bound inactive form or a GTP-loaded activated form. The activated form of KRas localizes on the membrane where it binds and activates downstream effector proteins such as Raf kinases. GDP-bound Ras can be activated by nucleotide exchange of GTP for GDP, a reaction that is catalyzed by guanine nucleotide exchange factors (GEFs). Ras is inactivated by hydrolysis of GTP, which is assisted by GTPase activating proteins (GAPs). It was recently reported that Ras can be tyrosyl phosphorylated by Src and dephosphorylated by SHP2 (PNAS 2014;111(36):E3785-94; Nat Commun 2015;6:8859). Here we have characterized the structural and functional alterations of Src-phosphorylated KRas to mechanistically explain the impact of tyrosyl phosphorylation on the GTPase cycle. Our NMR and MS analyses show that Src phosphorylates KRas at Tyr32 and Tyr64, which perturbs the chemical shifts of several residues in each of the two "switch" regions that mediate interactions with effectors and regulators. Using real-time NMR and biolayer interferometry (Octet) assays, we demonstrated the negative impact of KRas phosphorylation on the GTPase cycle as well as BRAF binding. Conversely, the SH2 domain containing inositol 5-phosphatase 2 (SHP2) dephosphorylates KRAS and reverses Src-induced phosphorylation. In vivo, either the pharmacologic inhibition or genetic ablation of SHP2 promotes cell death in several KRAS mutant cancers. Our findings reveal that altering the KRas GTPase cycle regulation via the balance of Src and SHIP2 activities may create a therapeutic vulnerability for pancreatic cancer.
Citation Format: Teklab Gebregiworgis, Christopher B. Marshall, Yoshihito Kano, Nikolina Radulovich, Ming-Sound Tsao, Michael Ohh, Mitsuhiko Ikura. Altering the regulation of KRAS GTPase cycle via Src and SHP2 creates a potential therapeutic vulnerability for pancreatic 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 4360.
Abstract 4365: Targeting the RhoA guanine nucleotide-exchange factor Syx for the treatment of glioblastoma
Authors: Lin Wan-Hsin , Feathers Ryan , Lewis-Tuffin Laura , Anastasiadis Panos 
Published: August 2018

Abstract
The RhoA GTPase is thought to play a crucial role in cancer development. Its activation is tightly controlled by numerous guanine nucleotide-exchange factors (GEFs). We previously showed that Syx, a RhoA-GEF, promotes junctional integrity in endothelial cells and governs cell polarity and directed migration in glioblastoma (GBM) cells. GBM is a grade IV glioma with a median survival of approximately 14 months. Importantly, the gene locus of Syx (Plekhg5) is located within chromosome 1p36, a region deleted in oligodendroglioma (a type II/III glioma) and associated with better prognosis, suggesting a role of Syx in GBM aggressiveness. Here we show that Syx is a potential target for the treatment of GBM. Knockdown of Syx resulted in altered expression of cell cycle regulators, including cyclins A, B, and E, cyclin-dependent kinase inhibitors (CDIs), namely p21 and p27, and mitosis modulators CDC20 and survivin. These defects resulted in G2/M arrest and dysfunction of cell division, leading to improper chromosome segregation and DNA double-strand breaks. However, DNA damage response could not be activated effectively for DNA repair, leading to cellular apoptosis. Consistent with these findings, we used an orthotopic patient-derived xenograft GBM model to show that Syx silencing results in decreased tumor growth accompanied by increased animal survival. Agents that cause DNA damage and/or disruption of DNA repair pathways are often used for cancer therapy. We thus tested the possibility of targeting Syx for GBM treatment, and showed that Syx knockdown in combination with temozolomide, a first-line drug for GBM, synergistically inhibit cell growth. In summary, this is the first study showing the role of Syx in GBM cell growth and that targeting this signaling pathway can be beneficial for GBM therapy.
Citation Format: Wan-Hsin Lin, Ryan Feathers, Laura Lewis-Tuffin, Panos Anastasiadis. Targeting the RhoA guanine nucleotide-exchange factor Syx for the treatment of glioblastoma [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 4365.
Abstract 4368: PAK4-NAMPT dual inhibition as a feasible strategy for treatment of resistant pancreatic neuroendocrine tumors
Authors: Mpilla Gabriel , Muqbil Irfana , Aboukameel Amro , Philip Philip A. , Senapedis William , Baloglu Erkan , Landesman Yosef , Kauffman Michael , Shacham Sharon , Mohammad Ramzi M. , Azmi Asfar S. 
Published: August 2018

Abstract
Our studies in pancreatic neuroendocrine tumor (pNET) cell lines demonstrate hyper-activation of the Rho GTPase effector p21 activated kinase 4 (PAK4) and the nicotinamide adenine dinucleotide (NAD) salvage pathway rate limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). The PAK4 protein is known to regulate a myriad of signaling proteins in the mTOR pathway including mTORC1, mTORC2, PI3K, and IGF-1. Similarly, NAMPT is recognized to regulate mTOR through energy sensor protein, AMPK. In this study, pNET cell lines QGP-1 and Bon-1 were subjected to either PAK4 RNA interference (RNAi), PAK4-NAMPT dual inhibitors (the clinical compound KPT-9274 or an analog KPT-7523) or the PAK4 specific inhibitor, PF-3738309 and NAMPT specific inhibitor FK866 in the presence or absence of mTOR inhibitors (everolimus or INK128). Gene expression profiling and phospho-proteomic analyses were performed to capture molecular changes post single or combination treatments. The anti-tumor activity of KPT-9274-everolimus was evaluated in a subcutaneous xenograft mouse model derived from QGP-1 and Bon-1 cells. PAK4 RNAi suppressed proliferation and restored everolimus sensitivity in pNET cell lines. The dual inhibitors were effective in reducing proliferation and inducing apoptosis. KPT-9274 or KPT-7523 could synergistically enhance the anti-tumor activity of everolimus or INK128 in pNET cell lines [CI &lt;1]. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers such as mTORC1, mTORC2, PI3K, ERK, FAK, RICTOR, β-catenin and IGF-1. In addition, KPT-9274 and analogs suppressed the steady state level of NAD and ATP. Importantly, KPT-9274 given i.v. or orally at the maximum tolerated dose (140 mg/kg, once/day for 5 days/week for 4 weeks) dramatically inhibited the growth of QGP-1 and Bon-1 tumors. This is the first study demonstrating the role of PAK4 and NAMPT in pNETs. KPT-9274 is currently in a Phase I trial of patients with advance solid malignancies or NHL (NCT02702492). Our pre-clinical work establishes a solid rationale for a Phase II clinical study of KPT-9274 and an mTOR inhibitor combination for the treatment of difficult to treat pNETs.
Citation Format: Gabriel Mpilla, Irfana Muqbil, Amro Aboukameel, Philip A. Philip, William Senapedis, Erkan Baloglu, Yosef Landesman, Michael Kauffman, Sharon Shacham, Ramzi M. Mohammad, Asfar S. Azmi. PAK4-NAMPT dual inhibition as a feasible strategy for treatment of resistant pancreatic neuroendocrine 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 4368.