bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2515: Comprehensive analysis of the histologically distinct components of an adenosquamous carcinoma of the lung
Authors: Krause Arthur , Filippo Maria R. De , Lorber Thomas , Savic Spasenija , Piscuoglio Salvatore , Ng Charlotte K. , Bubendorf Lukas 
Published: August 2019

Abstract
Background: Adenosquamous carcinoma (ASC) is a rare subtype of non-small-cell lung cancer, consisting of an adenocarcinoma (AC) and a squamous cell carcinoma (SCC) component. Little is known about the molecular makeup of the two components in ASC. In this study, we applied a comprehensive analysis including whole exome sequencing (WES) and RNA sequencing to understand the evolutionary relationship between the AC and SCC components of an ASC of the lung.
Methods:FFPE tumor tissue of three ASC patients was used in this study. Samples were stained with FastRed to visualize the nuclei. AC and SCC components were scratched separately from histological slides for DNA and RNA extraction. WES analysis was performed to assess the mutational profile and copy number alterations (CNAs). The transcriptome was investigated in each of the components using RNA sequencing.
Results:WES analysis of the AC and SCC components of one patient revealed a common trunk of 118 mutations, including driver mutations EGFR exon 19 deletion and TP53 p.192*, indicating a common clonal origin of the components and the presence of bona fide drivers in the common ancestor. AC shows more private mutations than SCC (234 vs 134). Potential drivers are private to AC included TP53 and AKT1 mutations, while TLX1 and TRBV5-1 mutations are restricted to SCC. AC and SCC have highly similar CNA profiles, suggesting that all CNAs are early evolutionary events of the ASC. Mutational signature of the truncal mutations is similar to that of the mutations private to AC, while mutations private to SCC showed a distinct pattern enriched in T&gt;G, suggesting that SCC may have derived from an AC ancestor cell. Transcriptomic profiling shows that genes related to oxidative phosphorylation, fatty acid metabolism and peroxisome pathways are highly expressed in AC, in contrast to genes related to epithelial-mesenchymal-transition, hedgehog signaling and IL6-JAK-STAT3-signaling pathways in SCC.
Conclusion:Macroscopic dissection and separate analysis of the histologically distinct components of an ASC of the lung demonstrated the clonal relatedness of the AC and SCC. The diverse phenotype of the components is associated with distinct genetic profiles and mutational signatures. Analysis of additional ASCs of the lung may reveal genetic and/or transcriptomic underpinnings of the phenotypes.
Citation Format: Arthur Krause, Maria R. De Filippo, Thomas Lorber, Spasenija Savic, Salvatore Piscuoglio, Charlotte K. Ng, Lukas Bubendorf. Comprehensive analysis of the histologically distinct components of an adenosquamous carcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2515.
Abstract 2526: Measuring DNA quantity, FFPE degradation, and genomic DNA contamination of ccfDNA in a single assay
Authors: Schagat Trista L. , Mook Jennifer , Steffen Leta , Wieczorek Doug , Knox Curtis 
Published: August 2019

Abstract
FFPE tumor biopsies are being increasingly used as a source of DNA for translational research in pursuit of personalized medicine. In addition, circulating cell-free DNA in liquid biopsy fractions shows promise as a means of tracking tumor burden, tumor regression, and/or cancer relapse. However, both sources come with significant DNA quality risks related to sample preparation that can result in downstream sequencing failures or false negatives. For FFPE samples, chemical fixation of the tissue crosslinks DNA, resulting in DNA fragmentation and damage that cannot be completely reversed. For liquid biopsy samples, contamination with genomic DNA can reduce sensitivity for detecting the tumor-specific fraction of ccfDNA. The ProNex® DNA QC Assay is a multiplex qPCR assay that provides both quantification and quality control for small or fragmented DNA samples. ProNex® DNA QC Assay includes a 75bp, 150bp, and 300bp target as well as an internal positive control. Unlike absorption, fluorescent DNA binding dyes, and electrophoresis-based methods, qPCR can be used to quantify specifically amplifiable DNA able to participate in downstream PCR or sequencing applications. The ratio of amplification at 75bp and 300bp sizes can be used to assess fragmentation of FFPE samples, which is correlated with improved coverage uniformity in NGS applications. With ccfDNA, the ratio can also be used to determine the degree of genomic DNA contamination and indicate when further clean-up is necessary prior to sequencing.
Citation Format: Trista L. Schagat, Jennifer Mook, Leta Steffen, Doug Wieczorek, Curtis Knox. Measuring DNA quantity, FFPE degradation, and genomic DNA contamination of ccfDNA in a single assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2526.
Abstract 2528: Mapping tumoral and immune heterogeneity in PD-1 responsive glioblastoma
Authors: Restrepo Paula , Yong Raymund , Laface Ilaria , Tsankova Nadejda , Gnjatic Sacha , Hormigo Adilia , Losic Bojan 
Published: August 2019

Abstract
Clonal evolution and the immune microenvironment in glioblastoma (GBM) ultimately determine the potential benefit of checkpoint inhibition. We present a case study of a 67- year-old patient who underwent a resection of a large right temporal GBM. The patient received standard-of-care treatment consisting of tumor resection, radiation therapy and concurrent temozolomide. Her tumor recurred as a gliosarcoma after 2 cycles of adjuvant Temozolomide. Subsequently, she received 26 cycles of a PD-1 checkpoint inhibitor and 20 cycles of bevacizumab, a VEGF-A inhibitor. She survived 25 months after diagnosis including six after immunotherapy and VEGF-A blockade was discontinued. We integrated RNA-seq and whole exome sequencing data from the primary tumor and several recurrent biopsies to characterize the genomic and molecular landscape within the context of clonal evolution. Specifically, we surveyed tumor-immune interactions by computing the mutational and neo-epitope tumoral burden, along with the magnitude and clonality of infiltrating lymphocytes using VDJ-sequencing. Furthermore, we intersected genomic instability measures with the regional gene expression profiles among the sectors. Finally, we integrated TCGA-GBM RNA-seq data to examine the expression of our patient sectors among the spectrum of known GBM variation. We found significant regional heterogeneity in the predicted neoantigen and infiltrating lymphocyte landscape, with a pronounced shift towards lower predicted immunogenicity and lower immune infiltration in all recurrent biopsies. We also observed profound large-scale immune variance among the regional sectors when examined in the context of TCGA. Overall, this case study quantifies intra-tumoral clonal and immune heterogeneity with multiregional glioblastoma omics data, providing reasonable priors for further assessing the efficacy of checkpoint inhibition for GBM.
Citation Format: Paula Restrepo, Raymund Yong, Ilaria Laface, Nadejda Tsankova, Sacha Gnjatic, Adilia Hormigo, Bojan Losic. Mapping tumoral and immune heterogeneity in PD-1 responsive glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2528.
Abstract 2530: Understanding cancer heterogeneity in relation to minor sub-clones at single cell profiling level in renal cell carcinoma
Authors: Villarreal Enrique I. Velazquez , Carpten John D. , Craig David W. 
Published: August 2019

Abstract
Renal cell carcinoma (RCC) is one of the most lethal urological malignancies that would benefit from understanding cancer heterogeneity to identify molecular signatures providing potential innovative therapeutic targets. Renal cell carcinoma is characterized by extensive cancer heterogeneity. Single cell sequencing has the potential to improve our understanding of cancer heterogeneity by providing clonotype detection. We examined cancer heterogeneity using single-cell copy-number analysis and clonotype detection in four renal cancer tumors. The technology used for processing single cell was 10x ChromiumTM Technology that provides detection of 100 Kb CNV events, calling clonotypes down to 10 of 1000 cell inputs. By processing each of the four samples it resulted 469 total cells from sample one where 268 were tumor and 171 were normal; sample two resulted with 888 cells where 51 were tumor and 820 were normal; sample three resulted with 673 total cells where 167 were tumor and 485 normal; finally, sample four resulted with 1298 cells where 511 were tumor and 758 normal. Genome-wide ploidy analysis of the four tumor cells showed variable median ploidies. The regional copy number was estimated by processing our data in 20 Kb cases of reads. Multiple sub-clones were identified in sample number one where four clusters of sub-clones characterized cancer heterogeneity. Fast maximum-likelihood (ML) genetic clustering and Bayesian Information Criterion (BIC) were implemented on sample one to select the optimal clustering solution and provide a better insight of sub-clonal evolution. These sub-clones reported events such as copy number changes on entire chromosomes arms. The single cell resolution provided the ability of variant detection where we identified VHL gene mutations that are consistent with recent reports that describe its role as a molecular signature of disease outcome and drug efficacy in RCC. In conclusion, our findings describe sub-clones with large-scale events that provide new insights in understanding cancer heterogeneity in RCC.
Citation Format: Enrique I. Velazquez Villarreal, John D. Carpten, David W. Craig. Understanding cancer heterogeneity in relation to minor sub-clones at single cell profiling level in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2530.
Abstract 2537: Targeting chromosomal passenger complex by disruption of INCENP function inhibits tumor progression in neuroblastoma
Authors: Sun Ming , Veschi Veronica , Lam Norris , Bagchi Sukriti , Xu Man , Mendoza Arnulfo , Liu Zhihui , Thiele Carol J. 
Published: August 2019

Abstract
Chromosomal passenger complex (CPC), which is composed of Aurora B and Survivin, INCENP and Borealin, regulates crucial mitotic events including chromosome alignment, segregation and cytokinesis during the mitosis. Disruption of CPC function by Aurora B and Survivin inhibition has been demonstrated to be effective at killing tumor cells and show promising results in many different cancer types including neuroblastoma (NB). However, chemical inhibition of either Aurora B or Survivin is unable to target CPC specifically due to off-target effects of Aurora B inhibitors on the other kinases and antiapoptotic activities of Survivin independent of this complex. In a chromatin-focused siRNA screen, we found that NB cells were particularly vulnerable to the silencing of INCENP, a gene encoding a key scaffolding and regulatory component of the CPC. In this study, we found that INCENP was highly expressed in NB cells and its expression levels were decreased upon Retinoic Acid (RA)-induced NB cell differentiation. Genetic silencing of INCENP reduced the growth of both MYCN single copy and MYCN amplified NB cell lines in vitro and led to significant decreases in NB xenograft growth and increases in murine survival in vivo. Elevated levels of INCENP were significantly associated with poor prognosis in primary NB tumors whereas low INCENP expression levels were predictive of better outcomes. Mechanistically, we found that INCENP depletion suppressed NB cell growth by inducing massive polyploidization, mitotic arrest, senescence and cell death (apoptosis). We also observed that in the majority of NB cell lines tested in vitro, cell death represented the primary cell fate after INCENP silencing due to a strong induction of DNA damage response and activation of the p53-p21 axis. Therefore, targeting INCENP phenocopies treatment with Aurora B inhibitor, providing a novel strategy to disrupt the activity of CPC and inhibit tumor progression in NB.
Citation Format: Ming Sun, Veronica Veschi, Norris Lam, Sukriti Bagchi, Man Xu, Arnulfo Mendoza, Zhihui Liu, Carol J. Thiele. Targeting chromosomal passenger complex by disruption of INCENP function inhibits tumor progression in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2537.
Abstract 2551: Inhibition of mTOR abrogates mitosis progression
Authors: Kuo Hsiao-Hui , Fang Chieh-Ting , Yih Ling-Huei 
Published: August 2019

Abstract
The mammalian target of rapamycin (mTOR) mediates the coordination of cell growth and cell cycle progression in response to nutrient supply. It is frequently activated in cancers and confers resistance to anti-cancer drugs. Accumulated studies have demonstrated that inhibition of mitotic kinases (PLK1 or aurora kinase A) enhances mTOR activities and the mTOR activation is associated with cell survival to anti-mitotic drugs. In this study, whether mTOR signaling is involved in mitosis progression is explored. Treatment of cells with mTOR inhibitors for 24 h resulted in the accumulation of G2 and mitotic cells and increased the percentage of mitotic cells with spindle abnormalities and chromosome missegregation. In addition, mTOR inhibitors sensitized cancer cells to taxol by enhancing apoptosis. Our results indicate that mTOR signaling pathway may be required for faithful mitosis progression and represent a potential resistance mechanism to the use of anti-mitotic drugs.
Citation Format: Hsiao-Hui Kuo, Chieh-Ting Fang, Ling-Huei Yih. Inhibition of mTOR abrogates mitosis progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2551.
Abstract 2552: Senescence induced by CDK4/6 inhibition facilitates anti-tumor T cell responses
Authors: Blevins Ashlyn , Mont Stacey , Lawrence Hunter , Saleh Nabil , Chen Sheau-Chiann , Richmond Ann , Vilgelm Anna 
Published: August 2019

Abstract
Cancer immunotherapies have shown remarkable clinical activity across several tumor types but responses have been modest in breast cancers. This is attributed to low levels of neo-antigens in breast tumors and immunosuppressive nature of mammary tumor microenvironment. Here we investigated if we can counteract these obstacles to an effective immunotherapy by inducing senescence in breast cancer cells. Senescence is one of the physiological stress response programs characterized by loss of proliferative potential and secretion of a variety of pro-inflammatory markers which promotes identification and removal of senescent cells by the immune cells. Here we hypothesized that senescence will stimulate anti-tumor immune response by establishing immune-permissive microenvironment. We utilized immunocompetent and humanized PDX-bearing mice to investigate senescence-induced modulation of tumor secretome proteome, transcriptome and immune cell recruitment and activity. An FDA-approved small molecule CDK4/6 inhibitor was used to induce senescence. We detected induction of multiple markers of senescence after CDK4/6 inhibitor treatment of cells and tumors. Senescent cells and tumors had increased secretion of chemokines CCL4, CCL5, CXCL9, CXCL10 and CXCL11 which facilitated T cell homing into the tumor. This was a result of their transcriptional induction by NF-κB. Consequently, we observed the dynamic enrichment of tumor immune microenvironment with T cells in tumors treated with CDK4/6 inhibitor. Furthermore, the recruitment of adoptively transferred ex-vivo activated anti-tumor T cells was significantly enhanced in tumors that were treated with CDK4/6 inhibitor. Finally, CDK4/6 inhibitor-treated tumors became responsive to T cell-activating immunotherapy with antibody agonists of T cell co-stimulatory receptors OX40 and 4-1BB. In summary, our findings suggest that CDK4/6 inhibition can facilitate T cell recruitment into the mammary tumors which can lead to an improved immunotherapy response. This pre-clinical study provides rationale for clinical development of CDK4/6 inhibitors and T cell agonists and uncovers the potential of senescence-inducing approach for sensitizing tumors to immune therapy.
Citation Format: Ashlyn Blevins, Stacey Mont, Hunter Lawrence, Nabil Saleh, Sheau-Chiann Chen, Ann Richmond, Anna Vilgelm. Senescence induced by CDK4/6 inhibition facilitates anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2552.
Abstract 2554: Branched chain amino acid transaminase 1 in claudin-low breast cancer
Authors: Reynen Lisa C. , Jones Robert , Moorehead Roger 
Published: August 2019

Abstract
Breast cancer, the most commonly diagnosed cancer in women, can be classified into five distinct subtypes. One subtype, claudin-low breast cancer, accounts for approximately 7% of the breast cancer cases and these tumors are aggressive and highly metastatic. RNA sequencing of human claudin-low breast cancers by other groups and RNA sequencing of a murine claudin-low mammary tumor cell line by our group has revealed that Bcat1 is significantly up-regulated in this breast cancer subtype. Bcat1 regulates the metabolism of branched chain amino acids and has been linked to numerous pathologies including heart disease, diabetes, and cancer. Based on this data we hypothesized that the expression of Bcat1 in claudin-low mammary tumors is driving the aggressive and metastatic nature of this cancer subtype and disrupting Bcat1 will deter these features. Elevated expression of Bcat1 in the murine claudin-low cell line RJ423, compared to the murine luminal mammary tumor cell line RJ345, has been confirmed at the mRNA and protein level. Bcat1 has been transiently down-regulated ~70% in RJ423 cells using siRNA and this suppression of Bcat1, contrary to the anticipated result, showed no effect on proliferation based on phospho-histone H3 immunofluorescence. However, when the cell population doubling time was investigated, a significant difference was seen between the RJ423 cell line and the cell lines with suppressed Bcat1 expression. To elucidate these contradicting results, cell cycle analysis using Bromodeoxyuridine and 7-AAD through flow cytometry is currently underway. RJ423 stably expressing Bcat1 shRNA and RJ345 stably expressing a Bcat1 expression vector are currently being selected. Further in vitro and in vivo studies will utilize these stably transfected cell lines. This study will determine whether further investigation into the effects of Bcat1 on claudin-low human breast cancer is prudent and if Bcat1 may be used as a therapeutic target.
Citation Format: Lisa C. Reynen, Robert Jones, Roger Moorehead. Branched chain amino acid transaminase 1 in claudin-low breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2554.
Abstract 256: Repurposing neuroleptic drug for brain tumor therapy
Authors: Kaushik Iti S. , Ranjan Alok , Schwettmann Blake , Srivastava Sanjay 
Published: August 2019

Abstract
Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Temozolomide (TMZ) is the main therapy for brain tumor but resistance to TMZ is the major cause of treatment failure. This resistance in tumor cells has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT). Pimozide (PMZ) is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. In our study, we observed that pimozide significantly reduced the viability of U87MG, U251MG, DAOY and GBM28 cell lines with an IC50 ranging from 11µM to 20µM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP. Western blot analysis resulted in the concentration dependent decrease in the expression of STAT3 signaling mainly targeting the anti-apoptotic markers BCl-XL, BCl-2 and Survivin etc in U87MG, U251MG, DAOY and GBM28 brain cancer cell lines. PMZ alone suppressed the growth of U87MG cells with an IC50 of 10µM, after 96 hours of treatment. On the other hand, treatment of U87MG cells with 750 µM of TMZ in combination with 10µM PMZ for 96 hours increased the killing of U87MG cells by 50% as compared to 10% when treated with TMZ. In addition, PMZ treatment reduced the survival of TMZ resistant U251R cells with an IC50 ranging from 15-20 µM after 24 h of treatment. Our results further demonstrated that oral administration of PMZ (25mg/kg) significantly inhibits the growth of brain tumors in an intracranial tumor model without any apparent signs of toxicity. It is important to note that PMZ is an FDA approved drug with no considerable toxicity. Overall, this study depicts that PMZ is a potential candidate to target brain tumors.
Citation Format: Iti S. Kaushik, Alok Ranjan, Blake Schwettmann, Sanjay Srivastava. Repurposing neuroleptic drug for brain tumor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 256.