bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2249: Detection of EGFR mutations in circulating cell-free DNA of non-small cell lung cancer patients by next-generation sequencing
Authors: Suzawa Ken , Tomida Shuta , Matsubara Takahiro , Ohashi Kadoaki , Maki Yuho , Yamamoto Hiromasa , Morita Mizuki , Soh Junichi , Asano Hiroaki , Tsukuda Kazunori , Kiura Katuyuki , Miyoshi Shinichiro , Toyooka Shinichi 
Published: July 2016

Abstract
[Background] Mutational analysis is essential for recent personalized therapeutic approaches of non-small cell lung cancer (NSCLC) patients. Circulating cell-free DNA (cfDNA) from plasma is an emerging topic as a tool for liquid biopsy and possibly enable repetitive genetic diagnosis or monitoring of cancer status. However, detection of cfDNA from the circulation still remains challenging because of its highly fragmented and low concentration nature. In this study, we analyzed cfDNA samples by targeted deep sequencing at high coverage.
[Materials and Methods] Twenty matched DNA samples were collected from metastatic NSCLC patients with EGFR mutation, which was detected by a clinical EGFR mutant enriched PCR assay using PNA-LNA PCR clamp method. These samples were extracted from tissue samples of fresh tumor tissue except one formalin fixed paraffin embedded (FFPE) sample (tDNA), and plasma samples (cfDNA). Mutation hotspots were enriched by multiplex PCR using the GeneRead DNAseq Targeted Panels V2 Human Tumor Actionable Mutations panel (QIAGEN, Hilden, Germany), followed by library construction, and sequenced on the MiSeq sequencer. Resulting data was analyzed using CLC Genomics Workbench and Genomics Server and mapped to the full human genome.
[Results and discussion] The mean read depth in target region was 59,000 reads. Matched EGFR driver mutations between cfDNA and tDNA were detected with an overall concordance of 25% (5 of 20 samples). The concordance rate of exon21 L858R point mutation, exon19 deletions and exon20 T790M point mutation were 32.5% (3 of 8 samples), 16.7% (2 of 12 samples), and 66.7% (2 of 3 samples), respectively. The mutant allele frequencies in cfDNA ranged from 0.1% to 44.5% (median, 0.3%). While further improvement is mandatory, these results suggest that targeted deep sequencing of cfDNA at high coverage may have a potential utility as a non-invasive mutational analysis. In addition, there seemed to be a tendency of better detection rate for point mutations (45.5%) than deletions (16.7%), while the difference didn't reach statistical significance (p = 0.19), which were corresponding to previous reports.
Citation Format: Ken Suzawa, Shuta Tomida, Takahiro Matsubara, Kadoaki Ohashi, Yuho Maki, Hiromasa Yamamoto, Mizuki Morita, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Katuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka. Detection of EGFR mutations in circulating cell-free DNA of non-small cell lung cancer patients by next-generation sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2249.
Abstract 2255: Evaluation of the diagnostic value of serum anti-cyclin B1 autoantibody as a biomarker in lung cancer
Authors: Xing Mengtao , Li Pei , Shi Jianxiang , Dai Liping , Li Jitian , Zhang Jianying 
Published: July 2016

Abstract
To detect the diagnostic value of cancer-associated autoantibodies in lung cancer, a panel of 9 tumor-associated antigens (TAAs) were used in this study. The TAAs were composed of p62, p16, Koc, p53, Cyclin B1, Cyclin E, Survivin, HCC1, and Rol-A full-length recombinant proteins. Enzyme-linked immunosorbent assay and immunoblotting were used to detect antibodies in 50 lung cancer sera with clinicopathological characteristics and 42 sera from normal individuals. Following, antibodies to Cyclin B1, survivin, p53 and HCC1 were selected and confirmed in another 62 sera from patients with lung cancer but without clinical date and evaluate the diagnostic value of these TAAs. The results showed that the positive rate of autoantibodies against nine selected TAAs (cyclin B1, survivin, HCC1,p53, KOC,p16,p62, RalA and cyclin E) reached 36%, 36%, 26%, 12%, 8%, 6%, 6%, 2%, 0% in 50 lung cancer sera and 4.8%, 2.4%, 0%, 0%, 2.4%, 4.8%, 2.4%, 2.4%, 4.8% in 42 normal sera, respectively. The AUC values for distinguishing lung cancers from normal sera were 0.767, 0.400, 0.567, 0.395, 0.230, 0.517, 0.635, 0.194, 0.411, respectively. These data suggest that cyclin B1, survivin, HCC1 and p53 has higher clinical diagnostic quality and value than other TAAs in lung cancer. In the confirmation group with 62 lung cancer sear, autoantibodies against these four TAAs were also significantly higher in patients with lung cancer (AUC values of 0.764,0.653,0.623 and 0.622, p&lt;0.05). Evaluation of the diagnostic value of these four TAAs in 50 sera from lung cancer patients with clinical characteristics, and results revealed that serum anti-cyclin B1, anti-survivin and anti-p53 autoantibodies significantly increased in patients with stage I but only serum anti-cyclin B1 increased in stage II and III lung cancer (p &lt;0.05, respectively), ROC curve analysis has shown that anti-cyclin B1 and anti-p53 autoantibodies can discriminate stage I lung cancer from normal controls with AUC value of 0.757,0.697, respectively (p&lt;0.01), and anti-survivin and anti-HCC1 autoantibodies failed to discriminate stage I lung cancer from normal controls. Our results suggest that these four TAAs has higher clinical diagnostic quality and value than other TAAs in lung cancer and serum cyclin-B1 may have the potential to serve as novel non-invasive diagnostic biomarkers in patients with lung cancer, especially in early stage lung cancer.
Citation Format: Mengtao Xing, Pei Li, Jianxiang Shi, Liping Dai, Jitian Li, Jianying Zhang. Evaluation of the diagnostic value of serum anti-cyclin B1 autoantibody as a biomarker in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2255.
Abstract 2259: Comprehensive evaluation of promising biomarkers for lung cancer risk prediction
Authors: Johansson Mattias A. , Taguchi Ayumu , Muller David , Hanash Samir , Brennan Paul 
Published: July 2016

Abstract
Introductory sentence indicating the purposes of the study:
Lung cancer will remain the number one cancer killer worldwide for the foreseeable future (Globocan 2012). Although low-dose CT screening has been shown to reduce mortality, there is an urgent need to improve risk prediction models to identify those subjects at high risk and most likely to benefit from screening in order its improve the screening efficacy (PMID: 23697514, 25372087).
Brief description of pertinent experimental procedures:
We have assembled a compendium of promising blood-based risk biomarkers for lung cancer that are currently being validated in order to identify a panel of validated risk markers for use in lung cancer risk assessment. Using pre-diagnostic serum samples from CARET cohort participants (current or former heavy smokers) we have recently validated pro-surfactant protein B (Pro-SFTPB) and Diacetyl spermine (DAS) as risk markers for non-small cell lung cancer (PMID: 26282655). Validation of additional markers from the compendium using Pro-SFTPB and DAS as anchor markers with further refinement of the risk prediction models is currently being performed in two large independent cohort studies (EPIC and NSHDS). Biospecimens from these cohorts include pre-diagnostic plasma from 550 former and current smoking lung cancer cases that were diagnosed within 5 years of blood draw, along with 1,100 matched controls.
Summary of the new, unpublished data and conclusion:
Preliminary data indicate that blood-based biomarkers of lung cancer risk have a strong potential to improve on questionnaire-based risk prediction models for lung cancer (PMID: 26282655). During the meeting we will present detailed results of the individual risk biomarkers and their associations with lung cancer risk up to 2 years prior to diagnosis, as well as an assessment of the extent to which they can improve traditional risk prediction models.
Citation Format: Mattias A. Johansson, Ayumu Taguchi, David Muller, Samir Hanash, Paul Brennan. Comprehensive evaluation of promising biomarkers for lung cancer risk prediction. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2259.
Abstract 2261: PKR and Jagged1 associated with lymph node metastasis in lung cancer
Authors: Pataer Apar , Hao Chuncheng , Correa Arlene M. , Weissferdt Annikka , Behrens Carmen , Wistuba Ignacio I. , Swisher Stephen G. 
Published: July 2016

Abstract
In the current study, we analyzed the association between lymph node metastasis and over 50 biomarkers in 319 NSCLC patients. We observed that tumor location and the protein expressions of Jagged1 and RNA-dependent protein kinase (PKR) have significantly association with the lymph node metastasis. We further investigated the mechanism of interaction between Jagged1 and PKR, and demonstrated that induction of PKR promotes Jagged1 protein degradation through proteasome system in lung cancer cells. We also found that combination of Jagged1 with PKR improved prognostic value in all stages NSCLC patients. However, combination of Jagged1 with PKR did not improve lymph node metastatic value. Taken together, our data suggest that PKR and Jagged1 are independent markers for predicting lymph node metastasis, and PKR may reduce lymph node metastasis partly by promote Jagged1 proteins degradation in NSCLC patients.
Citation Format: Apar Pataer, Chuncheng Hao, Arlene M. Correa, Annikka Weissferdt, Carmen Behrens, Ignacio I. Wistuba, Stephen G. Swisher. PKR and Jagged1 associated with lymph node metastasis in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2261.
Abstract 2264: Tumor fragmentation is a poor prognostic histologic biomarker for lung squamous cell carcinoma
Authors: Casanova Ruben , Soltermann Alex 
Published: July 2016

Abstract
Introduction: Lung squamous cell carcinoma (SCC) is the second most frequent histologic type of non-small cell lung carcinoma (NSCLC). Next to pTNM staging, grading is also important for histomorphologic classification of tumors into relevant prognostic groups. SCC forms cohesive tumor sheets of various sizes, ranging from large pushing boundaries to small detached clusters. The presence of small clusters such as single cells, tumor buds 15 cells) could also contain prognostic information and hence be pertinent for tumor grading. Herein we propose a computer-based morphometric analysis for the global assessment of lung SCC fragmentation.
Methods: Surgically resected lung SCC tumors (discovery tissue microarray cohort n = 208, 2 cores per patient; validation whole section cohort n = 99, 2 blocks per patient) were immuno-histochemically stained with pan-cytokeratin. Color-based segmentation (tumor epithelia brown, stroma blue-grey) allowed to separate tumor from stroma and to compute the number of tumor fragments. Associations with disease-free (DFS) and overall survival (OS) were assessed by univariate Cox regressions.
Results: Tumor fragments were defined as tumor clusters &gt;3000μm2 (circa &gt;15 cells) entirely surrounded by stroma. Criteria for high fragmentation were: &gt; 5 fragments summed over 2 TMA cores (range: 2-18, median = 5) and &gt; 700 fragments summed over 2 whole sections (range: 94-3988, median = 570). Respectively, 44% and 42% of the patients had highly fragmenting tumors in the discovery (D) and validation cohort (V), correlating with blood vessel infiltration (cc = 0.181, p&lt;0.001 (D); cc = 0.220, p = 0.029 (V)). High fragmentation was also associated with decreased OS (HR = 1.77, p = 0.001) and DFS (HR = 1.83, p = 0.027) in (D). This was confirmed in (V): OS (HR = 2.09, p = 0.004), DFS (HR = 2.60, p = 0.005).
Conclusions: We used an automated morphometric approach for unbiased scoring of tumor fragmentation on digitalized histological sections. This versatile method could potentially be applied to virtually any solid human carcinoma. Our analysis revealed that tumor fragmentation is a poor prognosticator for lung squamous cell carcinoma, e.g. due to increased likelihood of vessel infiltration.
Citation Format: Ruben Casanova, Alex Soltermann. Tumor fragmentation is a poor prognostic histologic biomarker for lung squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2264.
Abstract 2265: An integrated analysis of gene mutations and gene sets for predicting paclitaxel response in lung adenocarcinoma
Authors: Huang Chia-Yu , Chiu Yu-Chiao , Lu Tzu-Pin , Lai Liang-Chuan , Tsai Mong-Hsun , Hsiao Tzu-Hung , Chuang Eric Y. 
Published: July 2016

Abstract
Lung cancer is the leading cause of cancer death worldwide. A prevalent histological subtype of lung cancer is adenocarcinoma. Chemotherapies and targeted therapies have been developed to treat such malignancy. However, due to the heterogeneity of cancer genomes, drug responses vary considerably among patients and the average survival rate remains quite unsatisfactory. Therefore, integrated biomarkers for predicting drug responses are greatly needed. Addressing this, in the present study we aimed to develop a prediction model based on an integrated analysis of gene mutations and gene sets. Briefly, the two-tailed Student's t-test was performed to identify the gene mutations and gene sets of which activities were associated with drug sensitivity, and classification trees were derived from these genomic features. We applied the analysis to genomic datasets and drug sensitivity data from the Cancer Cell Line Encyclopedia (CCLE) and gene sets defined in the Molecular Signatures Database (MSigDB), and constructed a prediction model for response to paclitaxel, a widely used drug for cancers, in lung adenocarcinoma. Taking KRAS mutation as an example, we identified 20 and 15 drug response-associated gene sets in KRAS-mutant and KRAS-wild type cell lines, respectively. The two lists of gene sets were mutually exclusive, suggesting the need of building individual prediction models for groups of cancer subtypes. We then built a classification tree for each of the two groups and tested their prediction performance by leave one out cross-validation tests; ∼64% and ∼81% accuracy was achieved for KRAS-mutant and KRAS-wild type cell lines, respectively. Gene sets of “SIG_CHEMOTAXIS” and “PID_ERB_GENOMIC_PATHWAY” served as crucial nodes for the trees of KRAS-mutant and KRAS-wild type cells, respectively. In conclusion, we developed a novel method that integrates gene mutations and gene sets for predicting drug responses and demonstrated its high performance in lung adenocarcinoma. Our model is widely applicable to identify potent biomarkers for anticancer drugs in cancers and accelerate the realization of precision medicine.
Citation Format: Chia-Yu Huang, Yu-Chiao Chiu, Tzu-Pin Lu, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Hung Hsiao, Eric Y. Chuang. An integrated analysis of gene mutations and gene sets for predicting paclitaxel response in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2265.
Abstract 227: Leptin induces a fibroblast and endothelial cell crosstalk in tumor stroma
Authors: Lanier Viola 
Published: July 2016

Abstract
Background: The tissue microenvironment plays a major role in tumor development and recurrence. It is known that leptin secreted by cancer and adipose cells can modify the tumor stroma, which is composed of immune, fibroblast, and endothelial cells (EC). Leptin affects both normal and cancer associated fibroblasts. We have previously shown that leptin can modify EC directly via an increase of angiogenic features; which was linked to VEGFR signaling and Notch expression independent of VEGF. It is hypothesized that leptin induces a communication between fibroblast and endothelial cells via induction of Notch signaling, which may be related to exosome production.
Methods: Non-expressing Ob-R fibroblasts, and fibroblasts transfected with Ob-R plasmid, were used to investigate leptin's actions on Notch activation. Fibroblasts were challenged with leptin (0.6, 1.2, 6.2 nM) and an inhibitor of Notch signaling activation (DAPT). Fibroblast culture supernatants were added to and human umbilical vein endothelial cells (HUVEC) cultures. Notch proteins and RNA expression and molecular markers of activated fibroblasts and derived exosomes were determined via Western blot, RT-PCR, and multiplex analyses, respectively. EC angiogenic features were also determined.
Results: Our findings suggest that leptin induces fibroblast activation, which triggers the expression of Notch and the development of angiogenic features by EC.
Conclusions: A novel mechanism is proposed by which leptin promotes tumor stroma development via Notch activation and a crosstalk between fibroblasts and EC. Cancer therapies targeting leptin signaling could be a new strategy for interfering with cellular processes that promotes changes of tumor stroma towards a more aggressive tumor environment.
Citation Format: Viola Lanier. Leptin induces a fibroblast and endothelial cell crosstalk in tumor stroma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 227.
Abstract 228: Tumor suppressor functions of BNIP3 and mitophagy in pancreatic ductal adenocarcinoma
Authors: Chourasia Aparajita H. , Springer Maya Z. , Macleod Kay F. 
Published: July 2016

Abstract
The role of mitochondrial dysfunction in cancer is an emerging research field fuelled by the growing realization that mitochondrial dynamics are subject to oncogenic control, with mitochondrial biogenesis and mitophagy in particular modulated directly or indirectly by key oncogenes (c-Myc, B-Raf, K-ras) and tumor suppressors (p53, pRB). Work from our lab has focused on understanding how defects in mitophagy influence tumorigenesis with a particular focus on how BNIP3 loss during tumor progression influences disease outcome. BNIP3 functions as a dimer at the outer mitochondrial membrane to target mitochondria for degradation at the autophagolysosome through its interaction with processed LC3 at nascent phagophores. BNIP3 is a transcriptional target of HIF-1, E2F and FoxO3A transcription factors and is induced by activated Ras and suppressed by the RB and p53 tumor suppressors. Various studies have shown BNIP3 expression to be induced at early stages of human cancers and then lost as cancers progress to malignancy. In particular, epigenetic silencing of BNIP3 in human pancreas cancer has been correlated with reduced median survival. However, the mechanisms by which loss of BNIP3 may be contributing to cancer progression are not well delineated and a better understanding of how BNIP3-dependent mitophagy modulates pancreatic cancer in particular could provide new insight to the development of this deadly disease. We set out to examine how loss of BNIP3 affects the progression of pancreatic ductal adenocarcinoma using human cell lines and genetically engineered mouse models. We show that loss of BNip3 markedly accelerates tumor initiation and progression to invasive PDAC in the Pdx1-Cre;LSL-KRasG12D mouse model with metastases to the liver and lungs evident in BNip3 null mice but not in age-matched wild-type mice. Supporting a role for BNIP3 in suppressing pancreatic tumorigenesis, we also showed that re-expression of exogenous BNIP3 in Miapaca-2 cells (in which endogenous BNIP3 is silenced) resulted in reduced growth while knockdown of BNIP3 in CFPAC1 cells (that express BNIP3) promotes cell growth. Work described here examines the underlying mechanisms explaining these tumor suppressor functions of BNIP3 in pancreatic ductal adenocarcinoma.
Citation Format: Aparajita H. Chourasia, Maya Z. Springer, Kay F. Macleod. Tumor suppressor functions of BNIP3 and mitophagy in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 228.
Abstract 2284: Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR
Authors: Otani Sakiko , Sasaki Jiichiro , Masuda Kuniko , Okamoto Kazuya , Namubu Akiko , Matsumoto Toshihide , Tanaka Masumi , Ishihara Mikiko , Nakahara Yoshiro , Fukui Tomoya , Igawa Satoshi , Masuda Noriyuki 
Published: July 2016

Abstract
Background: Standard second-line chemotherapy against advanced non-small-cell lung cancer (NSCLC) is a single agent such as docetaxel, pemetrexed, or erlotinib (Erl). We recently reported that the combination of amrubicin (AMR) and Erl was clinically safe and effective for previously treated NSCLC patients. The purpose of this research is to confirm the experimental effectiveness of the combination and to investigate mechanism of the action.
Methods: We perform to evaluate the NSCLC cell lines proliferation inhibition by using XTT assay and to make two-dimension isobolograms for assessment of the combination effect. Flowcytemetry analysis (FACS) and Western blot analysis (WB) is also done in vitro. In vivo growth inhibition assay using subcutaneous model on SCID mice is performed. In addition, we measure intracellular concentration of amrubicinol(AMR-OH) which is converted as active metabolite from AMR in both cells treated with AMR alone and the combination.
Results: The combination of AMR and Erl had significant synergistic effect on EGFR wild type NSCLC cell line A549, while additive effect on EGFR mutant cell line PC-9. Sub G0-G1 population on FACS was significantly increased in A549 cells treated with combination. The combination activated apoptosis related proteins in WB. The strong growth inhibition of subcutaneous tumors on SCID mice was observed in the combination cohort. Intracellular concentration of AMR-OH was significantly increased in the combination than in AMR monotherapy.
Conclusion: The combination of AMR and Erl is synergistically induced apoptosis and growth inhibition on A549 cells via increasing intracellular concentration of AMR-OH. This combination may be a promising therapeutic option against advanced NSCLC with wild type EGFR.
Citation Format: Sakiko Otani, Jiichiro Sasaki, Kuniko Masuda, Kazuya Okamoto, Akiko Namubu, Toshihide Matsumoto, Masumi Tanaka, Mikiko Ishihara, Yoshiro Nakahara, Tomoya Fukui, Satoshi Igawa, Noriyuki Masuda. Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2284.