bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1706: Neoantigen frequency as an independent prognostic factor in patients with clear cell ovarian carcinoma (CCOC)
Authors: Matsushita Hirokazu , Hasegawa Kosei , Oda Katsutoshi , Yamamoto Shogo , Nishijima Akira , Imai Yuichi , Asada Kayo , Ikeda Yuji , Karasaki Takahiro , Fujiwara Keiichi , Aburatani Hiroyuki , Kakimi Kazuhiro 
Published: July 2017

Abstract
Aim: Neoantigens derived from tumor-specific somatic mutations are thought to be targets for antitumor immune responses. It has been reported that mutation/neoantigen burdens correlate with prognosis of certain cancers under checkpoint blockade immunotherapy. In clear cell ovarian carcinoma (CCOC), checkpoint inhibitors provided durable responses in a subset of patients. To test whether the same may apply in CCOC patients, who are not on immunomodulatory therapy, we investigated the number of mutations or neoantigens, and immune signature of CCOC by integrated molecular analysis.
Methods: We performed exome sequencing and expression array for 74 CCOC patients. Candidate neoantigens derived from mutations were identified by MHC class I binding prediction algorism (NetMHCpan v 2.8). Immune signature was assessed by gene ontology and gene set enrichment analyses for immune cell lineage or molecule genes. We also analyzed their relationships with clinical outcomes.
Results: Neither number of missense mutations nor neoantigens correlated with clinical outcomes in CCOC. However, we found neoantigen frequency defined here as the number of neoantigens per missense mutation correlated with clinical outcomes. A cox multivariate regression analysis demonstrated that high neoantigen frequency correlated with decreased progression free survival (PFS) and was an independent prognostic factor (p=0.032). Immune-related genes including those related to effector memory CD8 T cell were dominantly expressed in tumors with low neoantigen frequency. This may suggest that CD8 T cell-mediated immunity is constantly eliminating immunogenic subclones expressing neoantigens (immunoediting). In contrast, we observed increased ratio of CTLA-4 and PD-1 to CD8A expression in tumors with high neoantigen frequency. This may imply that restricted antitumor immunity by immunoinhibitory mechanism result in the limited immunoediting and poor prognosis
Conclusions: Neoantigen frequency underlying immunoediting in CCOC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for an immunomodulatory-based treatment.
Citation Format: Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi. Neoantigen frequency as an independent prognostic factor in patients with clear cell ovarian carcinoma (CCOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1706. doi:10.1158/1538-7445.AM2017-1706
Abstract 171: Targeting the tumor microenvironment: inhibition of carbonic anhydrase 9 impedes brain tumor initiating cell chemoresistance and delays glioblastoma growth in vivo
Authors: Boyd Nathaniel H. , Walker Kiera , McDonald Paul C. , Bevensee Mark O. , Gillespie Yancey G. , Nabors Burt , Dedhar Shoukat , Hjelmeland Anita B. 
Published: July 2017

Abstract
Brain tumor initiating cells (BTICs) are resistant to chemo- and radiotherapy, providing a reservoir for tumor recurrence and a desirable target for glioma treatments. Standard of care for glioblastoma (GBM; grade IV astrocytoma) includes the chemotherapeutic agent temozolomide, which prolongs life expectancy by months and is not curative. Prior studies suggested the efficacy of chemotherapies including temozolomide was increased by reducing expression of carbonic anhydrase 9 (CA9). CA9 is a hypoxia responsive gene elevated in tumors that is important for regulating intracellular pH and contributing to the acidic extracellular microenvironment. After confirming basal and hypoxia-induced expression of CA9 in GBM BTICs, we targeted CA9 activity with the small molecule inhibitor SLC-0111 alone or in combination with temozolomide. In multiple GBM BTIC lines, SLC-0111 reduced cell growth in vitro and showed additional benefit when used concurrently with temozolomide. Importantly, SLC-0111 inhibited the enrichment of BTICs after temozolomide treatment as determined via BTIC marker expression and neurosphere formation capacity. These data suggested the potential of SLC-0111 as a chemosensitizer, which we next evaluated in preclinical studies using a subcutaneous recurrent GBM model. GBMs treated with SLC-0111 in combination with temozolomide significantly regressed and the resulting in vivo growth delay was greater than that of temozolomide or SLC-0111 alone. Together, our data suggest that SLC-0111 can sensitize GBM BTICs to the chemotherapy temozolomide and significantly delay disease progression.
Citation Format: Nathaniel H. Boyd, Kiera Walker, Paul C. McDonald, Mark O. Bevensee, Yancey G. Gillespie, Burt Nabors, Shoukat Dedhar, Anita B. Hjelmeland. Targeting the tumor microenvironment: inhibition of carbonic anhydrase 9 impedes brain tumor initiating cell chemoresistance and delays glioblastoma growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 171. doi:10.1158/1538-7445.AM2017-171
Abstract 1711: Detection of circulating tumor cells for use as prognostic, predictive and pharmacodynamic biomarkers in neuroblastoma
Authors: Merugu Swathi , Tweddle Deborah 
Published: July 2017

Abstract
Introduction: Neuroblastoma (NB) is the commonest extracranial childhood solid tumour. New treatments and a better understanding of drug resistance are needed to improve survival. Circulating tumour cells (CTCs) may provide a source of tumour cells for genetic biomarkers, give insights into tumour load and serve as pharmacodynamic (PD) biomarkers for new treatments. In clinical diagnostics, slide based FISH is used to detect MYCN amplification in neuroblastoma tumours. As it is not possible to conduct slide based FISH on an entire blood sample due to the infrequency of CTCs in peripheral blood (1 in 106 leucocytes), an alternative method FISH-IS (in suspension) was used in the present study to detect MYCN gene amplification using the Imagestream imaging flow cytometer (ISx).
Aims: 1) To detect CTCs from blood and disseminated tumour cells (DTC) from bone marrow (BM) from NB patients using the (ISx) 2) To use these cells for genetic and PD biomarker studies for novel targeted therapies.
Methods: A panel of NB cell lines (n=6) cloned into neuronal (N) and substrate-adherent (S) types were used to determine expression of NB cell surface markers (GD2 and NCAM) using the ISx. Western blotting and fluorescence activated cell sorting (FACS) were used to validate NCAM and GD2 expression respectively. 25 paired NB patient blood and BM samples were analysed for CTCs and DTCs, 4 unpaired blood samples were analysed for CTCs and one unpaired BM sample was for DTCs using the ISx to detect GD2 +ve and CD45-ve cells.
Results: Using the ISx 80-90% of N-type cells immunostained positive for GD2 compared to 0.8 -10% of S-type cells confirmed by FACS. CTCs were detected in 21/29 patient samples and DTCs in 19/26 cases. The numbers of CTCs ranged from 10-522/ml blood and DTCs from 57-35,515/ml of bone marrow. After validating FISH-IS protocol on ISx using NGP and SHSY5Y cell lines, 4 NB patient DTC samples were analysed for MYCN amplification. 2/4 cases showed MYCN gene amplification consistent with results obtained on the primary tumour.
Conclusion: This the first study to show that DTCs and CTCs are detectable in NB patient samples using the ISx. Future work will involve further genetic characterisation and development of PD biomarkers for Phase I clinical trials.
Citation Format: Swathi Merugu, Deborah Tweddle. Detection of circulating tumor cells for use as prognostic, predictive and pharmacodynamic biomarkers in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1711. doi:10.1158/1538-7445.AM2017-1711
Abstract 172: Oxidative stress and hepatotoxicity induced by graphene oxide in Sprague-Dawley Rats
Authors: Patlolla Anita K. , Tchounwou Paul B. 
Published: July 2017

Abstract
Graphene oxide (GO) has been extensively explored as a promising nanomaterial for applications in biology because of its unique properties. Therefore, systematic investigation of GO toxicity is essential to determine its fate in the environment and potential adverse health effect. The aim of this study was to investigate the effect of graphene oxide on the induction of reactive oxygen species (ROS), the activity of certain liver enzymes (Alanine ALT, Aspartate AST, alkaline phosphatases ALP), and concentration of lipid hydroperoxide (LHP) in serum and histopathological evaluation of liver tissue in Sprague-Dawley rats. Four groups of five male rats were orally administered GOs, once a day for five days, with doses of 0, 10, 20 and 40 mg/Kg GO. A control group was also made of five rats. Blood and liver were collected 24 h after the last treatment following standard protocols. GO’s exposure increased the induction of ROS, the activities of the liver enzymes (ALT, AST, ALP), concentration of lipid hydroperoxide (LHP) and morphological alterations of the liver tissue in exposed groups compared to control. The highest two doses, 20 and 40 mg/kg, showed statistically significant (p &lt; 0.05) increases in the induction of ROS, activities of ALT, ALP , LHP concentration, and morphological alterations of liver tissue compared to control. However, AST activity showed no effect. Taken together, the results of this study demonstrate that GO is hepatotoxic, and its toxicity may be mediated through oxidative stress.
Citation Format: Anita K. Patlolla, Paul B. Tchounwou. Oxidative stress and hepatotoxicity induced by graphene oxide in Sprague-Dawley Rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 172. doi:10.1158/1538-7445.AM2017-172
Abstract 1731: Analysis of prostate cancer circulating tumor cells at the mRNA and protein level using a microfluidic graphene oxide chip
Authors: Kozminsky Molly , Day Kathleen C. , Hiles Guadalupe Lorenzatti , Fouladdel Shamileh , Azizi Ebrahim , Day Mark L. , Morgan Todd , Nagrath Sunitha 
Published: July 2017

Abstract
While the relative five-year survival rate for men with localized prostate cancer is nearly 100%, it plummets to 28% in the case of distant metastases. This underscores the importance of investigating those cells able to spread and form these metastases: circulating tumor cells (CTCs). Though rare and surrounded by other blood cells, CTCs can be isolated using the sensitive nanomaterial-based microfluidic technology the graphene oxide (GO) Chip. Whole blood samples from 54 prostate cancer patients were obtained with consent and processed on parallel chips for immunofluorescence and RNA analysis. All of the samples were analyzed for CTC enumeration, where captured cells were stained for cytokeratin 7/8 (CK), CD45, and DAPI. CTCs were identified as DAPI+/CK+/CD45- cells. CTCs were detected in all of the samples. Interestingly, 25 samples showed CTC clusters ranging from 2-10 CTCs per cluster. To explore the potential role of EGFR in metastatic progression and CTC survival, a subset of samples was also assayed for EGFR expression with 9/10 samples showing EGFR+ CTCs. RNA extracted from a parallel device was reverse transcribed to cDNA. The cDNA was analyzed via qPCR for expression levels of 96 genes of interest, including housekeeping genes; epithelial and mesenchymal genes; oncogenes and tumor suppressor genes; prostate specific genes; extracellular matrix and inflammatory genes; and others. The results show our ability to examine RNA from CTCs to examine the role of relevant pathways in the cells in transit. With analysis capabilities at both the RNA and protein levels, the GO Chip is an example of a clinically relevant microfluidic technology.
Citation Format: Molly Kozminsky, Kathleen C. Day, Guadalupe Lorenzatti Hiles, Shamileh Fouladdel, Ebrahim Azizi, Mark L. Day, Todd Morgan, Sunitha Nagrath. Analysis of prostate cancer circulating tumor cells at the mRNA and protein level using a microfluidic graphene oxide chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1731. doi:10.1158/1538-7445.AM2017-1731
Abstract 1739: Analysis of EML4-ALK fusion transcripts in plasma and platelets to monitor response to crizotinib in EML4-ALK positive non-small cell lung cancer patients (NSCLC)
Authors: Aguado Cristina , Teixido Cristina , Gimenez-Capitan Ana , Gil Maria de los Llanos , Rodriguez Sonia , Viteri Santiago , Karachaliou Niki , Aldeguer Erika , Peg Vicente , Alonso Lidia , Molina-Vila Miguel Angel , Rosell Rafael 
Published: July 2017

Abstract
Background: Rearrangements in anaplastic lymphoma kinase (ALK) gene can be detected in 5-7% of EGFR and KRAS wild-type advanced NSCLC patients (p). Fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) are currently used for screening but are unable to identify the specific fusion partner and are unpractical to monitor clinical responses due to difficulty of obtaining rebiopsies. The RT-PCR technique has the potential to overcome this pitfall and allow patient monitorization in blood.
Methods: A total of 405 formalin-fixed paraffin-embedded (FFPE) samples from advanced NSCLC were analyzed by ALK IHC (Ventana D5F3) and FISH (Vysis). Positive patients were confirmed by RT-PCR and submitted to Sanger in order to identify the variant. In a subset of 36 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, fusion transcripts were analyzed by RT-PCR in mRNA purified from plasma and platelets and correlated with clinical response.
Results: ALK IHC was analyzed in 405 NSCLC patients and 37 tested positive (9.1%) whereas 25 (7.7%) were identify as translocated by FISH (n=323). ALK fusion transcripts were analyzed by RT-PCR and a new fusion variant of ALK was identified. A total of 36 p benefited from crizotinib treatment, including the p with the new variant. Monitoring of EML4-ALK fusion transcripts in the plasma ad platelets of 35 ALK positive patients revealed a good correlation with clinical outcome to crizotinib treatment, with the fusion transcripts becoming undetectable in p with good clinical responses.
Conclusions: Analysis of ALK fusion transcripts in mRNA purified from plasma and platelets can have a value in patients with no biopsy available and to monitor the course of the disease.
Citation Format: Cristina Aguado, Cristina Teixido, Ana Gimenez-Capitan, Maria de los Llanos Gil, Sonia Rodriguez, Santiago Viteri, Niki Karachaliou, Erika Aldeguer, Vicente Peg, Lidia Alonso, Miguel Angel Molina-Vila, Rafael Rosell. Analysis of EML4-ALK fusion transcripts in plasma and platelets to monitor response to crizotinib in EML4-ALK positive non-small cell lung cancer patients (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1739. doi:10.1158/1538-7445.AM2017-1739
Abstract 176: Early development of GMC1, a novel molecule targeting FKBP52 for the treatment of hormone-refractory prostate cancer
Authors: Xie Huan , Ekpenyong Oscar 
Published: July 2017

Abstract
Purpose: GMC1 directly inhibits FKBP52, effectively blocking androgen receptor dependent gene expression and androgen-stimulated proliferation. This make it an attractive option for the treatment of hormone-dependent and hormone-independent prostate cancer. This study investigated an analytical method for GMC1 quantification, pre-formulation characteristics of GMC1, and developed intravenous formulations for the evaluation of GMC1 in animal models.
Method: An LC/MS/MS method for the quantification of GMC1 in solution, plasma and urine was developed, validated and applied to the determination of the stability, log P, plasma protein binding and solubility of GMC1 in various solvents. Liposomal formulations and co-solvent systems with various ratios of high capacity vehicles were formulated and the optimal formulation applied, at 2 mg/kg single IV bolus dose, to the pharmacokinetic study of GMC1 in a rat model.
Result: The intra- and inter-day accuracy (%RE) and precision (%CV) of the LC/MS/MS method ranged from 1.6 – 11.7 % and 1.4 – 8.8 %, respectively. GMC1 is stable in solid and solution state, moderately lipophilic (log P = 1.38 ± 0.05), poorly water soluble (0.4 ± 0.01 mg/mL), and highly plasma protein bound (&gt;71%). The optimal formulation consisting of PEG 300 and Labrasol ® (1:1, v/v) allowed us to achieve a GMC1 concentration of 10 mg/mL, and tolerated an aqueous environment. GMC1 has a tri-exponential disposition with a Cmax of 7.6 ± 1.97 mg/L, clearance of 0.53 L/kg/hr, α-distribution, β-phase and terminal elimination half-lives of 0.1 ± 0.04 hr, 1.2 ± 0.34 hr, and 19.7 ± 5.09 hr respectively.
Conclusion: The LC/MS/MS method, formulations and pharmacokinetic study can be applied to the pre-clinical and clinical development of GMC1.
Grant Support: This work was performed under funding from NIH/NIGMS grant (5SC3GM102018) and NIH/NIMHD/RCMI grant (5G12MD007605).
Citation Format: Huan Xie, Oscar Ekpenyong. Early development of GMC1, a novel molecule targeting FKBP52 for the treatment of hormone-refractory prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 176. doi:10.1158/1538-7445.AM2017-176
Abstract 1765: Molecular and immunological characterization of non-small cell lung cancer harboring cMET alterations
Authors: Saigi Maria , Pereira Carolina , Pros Eva , Brambilla Elisabeth , Nadal Ernest , Sánchez-Céspedes Montse 
Published: July 2017

Abstract
Purpose: To explore the correlation between the expression of immunological biomarkers in a subset of NSCLC tumors presenting cMET activation.
Methods: We retrospectively reviewed 200 tumor samples from a cohort of patients diagnosed with NSCLC in 3 different hospitals, from Spain and France. cMET activation was defined by the presence of one or more of the following criteria: 1- cMET mutations inducing exon 14 skipping (METex14), 2- cMET amplification, assessed by FISH 3- cMET overexpression, assessed by immunohistochemistry (IHC). METex14 mutations were determined by genomic sequencing and RT-PCR. FISH was interpreted according to Capuzzo scoring system, considering 5 or more gene copies as the mean value for positive amplification. Concurrent genetic alterations in EGFR and ERBB2 tyrosine kinase receptors were also determined. PD-L1 expression and density of tumoral infiltrating CD8+ lymphocytes were assessed by IHC. Statistical correlation analysis was performed by Chi-square and Fisher’s exact test.
Results: METex14, cMET amplification and cMET overexpression were detected in 2%, 7.8% and 31% of tumors, respectively. Histological subtypes included: 70% adenocarcinoma, 20% squamous cell carcinoma, 8% large cell, 2% pulmonary sarcomatoid. Curiously, one of the METex14 adenocarcinoma was concurrent with ERBB2 amplification. Those tumors harbouring METex14 or cMET amplification were correlated with positivity for PD-L1 expression (p = 0.02). However, this association was not observed in cMET overexpressed tumors.
Conclusions: We observed a direct correlation between PD-L1 positivity and METex14 or cMET amplification. Functional analysis and a large cohort of tumors are required to better characterize the potential role of cMET pathway in the regulation of PD-L1 expression.
Citation Format: Maria Saigi, Carolina Pereira, Eva Pros, Elisabeth Brambilla, Ernest Nadal, Montse Sánchez-Céspedes. Molecular and immunological characterization of non-small cell lung cancer harboring cMET alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1765. doi:10.1158/1538-7445.AM2017-1765
Abstract 1768: A practical tool for probing protein glycosylation in clinical samples: Application to characterizing subtypes of MUC5AC glycosylation in distinct subsets of pancreatic cancer patients
Authors: Hsueh Peter Y. 
Published: July 2017

Abstract
Glycans are critical to protein biology and are useful as disease biomarkers. Many studies of glycans rely on clinical specimens, but the low amount of sample available for some specimens limits the experimental options. We have a method to obtain information about protein glycosylation using a minimal amount of protein, and we applied it to the study of biomarkers in the blood plasma of pancreatic cancer patients. The method works by treating proteins that were captured by antibody microarrays (2.2 x 2.2 mm) with exoglycosidases to successively expose underlying features, and then probing the native or exposed features using a panel of lectins or glycan-binding antibodies. We use an algorithm to interpret the data and provide predictions about the glycan motifs that are present in the sample. We applied the method to the analysis of the glycosylation of a biomarker, MUC5AC, found in the plasma of patients with pancreatic cancer. An O-linked glycan on MUC5AC that is elevated in the plasma of about 75% of patient had mostly 2,3 linked sialic acid on type-1 N-acetyl-lactosamine (LacNAc), whereas other glycans on MUC5AC had a 2,6 linkage of sialic acid on type-2 LacNAc. Another glycan, fucosylated and sialylated/sulfated type-2 LacNAc, which is elevated in distinct subset of patients, was on N-linked glycans, representing an unusual finding of N-linked glycans on mucins associated with cancer. Further developments are enabling the testing for consistent structural features associating with subtypes of cancer, which could improve our ability to detect and target the subtypes. The on-chip glycan modification and probing (on-chip GMAP) method provides a platform for analyzing protein glycosylation in clinical specimens and could facilitate the characterization and discovery of glycan biomarkers.
Citation Format: Peter Y. Hsueh. A practical tool for probing protein glycosylation in clinical samples: Application to characterizing subtypes of MUC5AC glycosylation in distinct subsets of pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1768. doi:10.1158/1538-7445.AM2017-1768