bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 679: Serine/threonine kinase inhibitors on improving symptoms of neuroendocrine tumor
Authors: Liu I-Hua , Ding Yusian , Liou Chiung-Wen , Chang Jia-Ming 
Published: July 2017

Abstract
Recently, neuroendocrine tumors (NETs) are increased and mostly occurred in gastrointestinal tract and lung in the worldwide. It secretes functional hormones and non-functional neural transmitters to affect patients unwell so called carcinoid syndrome. In clinically, surgical removal and somatostatin treatment are used to ease the syndrome by NETs. A new strategy for advanced NETs is used by targeting mTOR signaling and neovascularization. In 2011, Everolimus, an mTOR inhibitor, was approved for the treatment of progressive NETs of pancreatic origin in patients with unresectable, locally advanced or metastatic disease, but safety and effectiveness of everolimus have not been established. In this study, low dose of mTOR inhibitor was investigated for capability in modifying the carcinoid syndrome. In an NCI-H727 NET xenograft model, the level of chromogranin A (CgA) was determined in accordance with tumor volume. With multiplexing the serum hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin were lowered in tumor-bearing mice, but they were rebound when animals treated with Everolimus. Another mTOR inhibitor INK 128 had no apparent tumor inhibition in the same model with doses ranged from 0.25-1 mg/kg. There was no change in the level of CgA in INK128-treated tumor-bearing mice but alpha-MSH level was restored compared with normal mice at a dose-dependent manner. In conclusion, we discovered that low dose of mTOR inhibitor could modify the carcinoid syndrome, where alpha-MSH and beta-endorphin may serve as biomarkers for prognoses of mTOR treatment.
Citation Format: I-Hua Liu, Yusian Ding, Chiung-Wen Liou, Jia-Ming Chang. Serine/threonine kinase inhibitors on improving symptoms of neuroendocrine tumor [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 679. doi:10.1158/1538-7445.AM2017-679
Abstract 68: Methotrexate prevents primary immune responses against recombinant immunotoxin in murine models
Authors: King Emily M. , Mazor Ronit , Pastan Ira 
Published: July 2017

Abstract
Recombinant immunotoxins (rITs) are composed of a tumor antigen-targeting antibody fragment fused to a portion of Pseudomonas exotoxin A. rITs have been effective in clinical trials for patients with hematologic malignancies. The CD22 targeting rIT Moxetumomab Pasudotox has achieved overall response rates of 86% and complete remission rates of 46% in patients with relapsed-refractory Hairy Cell Leukemia. However, the therapeutic efficacy of rITs against solid tumors is limited by their immunogenicity in immune-competent patients. In clinical trials to treat mesothelioma patients with SS1P, a rIT targeting mesothelin, 90% of patients developed neutralizing antibodies against SS1P after one cycle of treatment. When immunosuppressive chemotherapy and SS1P were combined, more cycles of rIT could be given and several patients with advanced chemo-refractory mesothelioma had striking tumor regressions. This implicates high therapeutic potential for rITs against solid tumors once immunogenicity is surmounted.
Methotrexate (MTX) is a folate antagonist which interferes with purine biosynthesis, and is used to treat osteosarcomas and other cancers. MTX also interferes with T cell responses and is used to treat autoimmune diseases. Based on its immunosuppressive properties, Joly et al. demonstrated that low-dose MTX prevented the formation of ADAs against recombinant human alglucosidase alfa in mice in an antigen-specific manner. We hypothesized that MTX would similarly prevent the formation of ADAs against rITs in an antigen-specific manner. To test our hypotheses, mice were treated with the mesothelin-targeting rIT RG7787 with or without MTX given 0, 24, and 48 hours after RG7787 treatment. Serum was collected and anti-RG7787 ADAs were measured by direct ELISA. We found that six doses of RG7787 combined with low dose MTX (1 mg/kg) inhibited the formation of ADAs against RG7787. This inhibition was sustained through six challenges with RG7787 without additional MTX. Further, we found that immunization with RG7787 plus MTX induced RG7787-specific tolerance, and had no effect on the ADA response against a second protein, ovalbumin.
We conclude that combination of MTX and RG7787 is effective at preventing primary immune responses in a durable, antigen-specific manner. We propose to combine this agent in immune-competent cancer patients receiving rIT therapy to prevent rIT immunogenicity.
Citation Format: Emily M. King, Ronit Mazor, Ira Pastan. Methotrexate prevents primary immune responses against recombinant immunotoxin in murine models [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 68. doi:10.1158/1538-7445.AM2017-68
Abstract 681: Methylomics profiling reveals epigenetically silenced HS3ST2 sensitize IL6 signaling and confers poor prognosis of ovarian cancer
Authors: Huang Rui-Lan , Chan Hsiang-Ju , Chen Lin-Yu , Hsu Yaw-Wen , Chao Tai-Kuang , Su Po-Hsuan , Weng Yu-Chun , Yuan Chiou-Chung , Lai Hung-Cheng 
Published: July 2017

Abstract
The attempts of target therapy in ovarian cancer therapy mostly fail. There is a need of biomarkers for better patient stratification in clinical trials. Epigenetics is a driving force for cancer development and may serve as a molecular marker of disease. The present study was to analyze the clinical relevance of methylation phenotypes and figure out the mechanism in ovarian cancer. We integrated the analysis using public dataset of epigenomics and transcriptomics, and our hospital-based methylomic database and tissue arrays of patients diagnosed with epithelial ovarian cancers (EOC). Bioinformatics results were verified and validated in cell lines and clinical samples. From 25 genes, we identified even genes, ADRA1A, CD248, HS3ST2, NEFH, IGSF21, POU4F2, and TWIST1, of which hypermethylation was significantly related to the poor overall survival (OS). The association of NEFH and HS3ST2 hypermethylation and poor 5-year OS was validated in our independent dataset and TCGA database. The NEFH/HS3ST2 hypermethylated signature was an independent risk factor for 5-year OS (adjusted Hazard ratio = 2.93, 95% confidence interval = 1.25 to 6.85, P = 0.013). In vitro experiment re-expressing HS3ST2 repressed migration and invasion, and suppressed IL-6 signaling pathways. The combination of hypermethylation of HS3ST2 and high expression of IL-6 confers the worse outcome. Our data suggested that methylation of NEFH/HS3ST2 constituted a poor prognostic signature of ovarian cancer. The sulfation status of proteoglycan modified by HS3ST2 implicates an intrinsic sensitivity of ovarian cancer cells to IL-6, which shed a new light on the application of HS3ST2 as a biomarker for personalized medicine of targeting IL-6.
Note: This abstract was not presented at the meeting.
Citation Format: Rui-Lan Huang, Hsiang-Ju Chan, Lin-Yu Chen, Yaw-Wen Hsu, Tai-Kuang Chao, Po-Hsuan Su, Yu-Chun Weng, Chiou-Chung Yuan, Hung-Cheng Lai. Methylomics profiling reveals epigenetically silenced HS3ST2 sensitize IL6 signaling and confers poor prognosis of ovarian 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 681. doi:10.1158/1538-7445.AM2017-681
Abstract 690: Identifying the genetic basis of stage 4S neuroblastoma
Authors: Vaksman Zalman , McDaniel Lee D. , Diamond Maura , Maris John M. , Diskin Sharon J. 
Published: July 2017

Abstract
Introduction: The 5 year mortality rate for stage 4 metastatic neuroblastoma (NBL) is ~50%; however, the stage 4S subset of NBL is typically classified as low-risk with tumors exhibiting spontaneous regression. To date, the underlying genetic mechanisms influencing this distinct phenotype remain unknown.
Method: To identify genetic determinants specific to the 4S phenotype, we performed genome-wide association study (GWAS) analyses. Blood DNA samples from 6,195 NBL patients and 11,384 non-NBL controls were genotyped using Illumina SNP arrays. European ancestry subjects were selected for inclusion in a discovery [stage 4S (n=148), stage 4 (n=996), non-NBL controls (n=9,923)] or replication cohort [stage 4S (n=76), stage 4 (n=608), non-NBL controls (n=1,461)]. Following imputation using 1KG Phase 3, we conducted case:case comparisons including stage 4S vs. 4 and stage 4S vs. 1, followed by comparisons of NBL cases in each group to matched non-NBL controls. Variants uniquely associated with 4S NBL were defined as those meeting the following criteria: (1) stage 4S vs. 4 meta P &lt; 5.0 x 10-5 and P &lt; 0.005 in the discovery cohort (2) 4S vs. non-NBL control P &lt; 0.05 and (3) either not significant (P &gt; 0.05) or odds ratio in the opposite direction in 4 vs. non-NBL controls.
Results: 4S-specific variants that met our criteria spanned multiple regions with several harboring genes important to neuronal function including 9q34 (SARDH/DBH; rs2502746), 1p32.2 (KCNH1; rs12122529), 1p34 (KCNQ4; chr 1:41317634), 7q34 (CNTNAP2; rs79403134) and 2q24.1 (KCNJ3; rs78829625). At the 9q34 locus, rs2502746 showed further evidence as an expression quantitative trait locus (eQTL) for Dopamine Beta-Hydroxylase Antisense RNA1( DBH-AS1 P = 1.9 x 10-5 sun-exposed skin) and Sarcosine Dehydrogenase SARDH expression (P = 2.5 x 10-6 whole blood). Other 4S-specific loci observed include 3q27.3 (rs113207181), 8p21.3 (rs12548388), and 15q12 (rs62189512). Notably, none of the previously identified NBL susceptibility loci were found to be associated with 4S NBL in the 4S vs. non-NBL control comparison, suggesting a unique genetic basis for this enigmatic subset.
Discussion: Although a unifying mechanism underlying 4S NBL has yet to be identified, our results suggest a potential role for ion-channel and neuronal function genes. Ongoing efforts include investigating the role these genes and associated pathways play in NBL, including an integrative genomic, epigenomic and transcriptome analysis of stage 4 and 4S NBL.
Citation Format: Zalman Vaksman, Lee D. McDaniel, Maura Diamond, John M. Maris, Sharon J. Diskin. Identifying the genetic basis of stage 4S 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 690. doi:10.1158/1538-7445.AM2017-690
Abstract 695: Targeted nanoparticle therapy for poor prognosis Ewing’s sarcoma
Authors: Kang HyungGyoo , Nagy Jon , Samulak Julia , Triche Timothy 
Published: July 2017

Abstract
Targeted nanoparticles have shown the potential to deliver anticancer drugs to cancer cells selectively and thus to overcome unexpected cytotoxicity and limited efficacy of chemotherapy caused by non-selective delivery to normal cells. However, the optimal formulation of targeted nanoparticles for actual translational applications has not been established. By refining early formulations and after extensive testing, we have created an optimized targeted delivery system, HPLNs (Hybrid Polymerized Liposomal Nanoparticles) and demonstrated that this new, targeted nanoparticle technology overcomes many of these deficiencies. This technology has tremendous potential for treating virtually any type of cancer. The goal of our present study was to determine the efficacy and toxicity of this novel targeted nanoparticle in the treatment of Ewing’s Sarcoma, a rare and highly lethal cancer of children and young adults. The efficacy of this targeted delivery system was compared to 1) administration of the free drug and 2) the drug in untargeted nanoparticle form. Our studies have shown that HPLN-Dox targeted with human antiCD99 antibodies can successfully inhibit the growth of Ewing’s Sarcoma in murine models without any detectable off-target toxicity. The deliverable for our study was to demonstrate that the effectiveness of doxorubicin in the treatment of recurrent Ewing’s sarcoma could be dramatically improved when encapsulated in human antiCD99 antibody targeted HPLNs. At the same time, toxic side effects normally seen with free drug was not detectable. Success with human anti-CD99 antibodies targeted HPLNs containing Doxorubicin was then easily adapted to other tumor types (Leukemia, Prostate or Pancreatic cancers) and other payloads such as irinotecan, EWS-FLI1 specific ASOs, siRNA and CRISPR/Cas9 targeting the ETS domain of the chimeric EWS-ets gene found in all Ewing sarcoma. In conclusion, our study showed a potential of targeted HPLN as a selective delivery vehicle of cytotoxic payloads to cancers and this technology is then easily adapted to other tumor types and virtually any small molecule therapeutic.
Citation Format: HyungGyoo Kang, Jon Nagy, Julia Samulak, Timothy Triche. Targeted nanoparticle therapy for poor prognosis Ewing’s sarcoma [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 695. doi:10.1158/1538-7445.AM2017-695
Abstract 711: Mechanistic implications of COL1A1 as a prostate cancer biomarker
Authors: Jedinak Andrej , Vuichoud Camille , El-Hayek Andrew , Kaplan Katherine , Savage Jason , Prophet Sarah , Feldman Adam S. , Camphausen Kevin A. , Loughlin Kevin R. , Moses Marsha A. 
Published: July 2017

Abstract
Prostate cancer (PCa) is the second most frequently diagnosed form of male cancer and shares similar symptoms with BPH (Benign Prostate Hyperplasia), a disease characterized by prostate enlargement. Elevated levels of prostate-specific antigen (PSA) can be observed with either benign or malignant growth of the prostate and therefore cannot effectively discriminate between these two prostate diseases. Currently, a test that sensitively and accurately distinguishes between BPH and localized prostate cancer does not exist creating an urgent need for novel biomarkers that can successfully distinguish between these two prostate diseases. The goal of this study was to identify and validate non-invasive urinary biomarkers that distinguish between BPH and PCa. Our previous proteomic study identified elevated levels of several proteins, including EGF (epidermal growth factor), HE-4 (human epididymis protein 4), COL1A1 (collagen, type I, alpha 1) and other proteins in the urine of PCa patients compared to urine samples from patients with BPH. In this current study we have analyzed and validated the presence of EGF, HE-4 and COL1A1 by enzyme-linked immunosorbent assay (ELISA). Our ELISA experiments revealed that COL1A1 was significantly (P &lt; 0.002) elevated in the urine of patients diagnosed with early or localized PCa vs. BPH. In vitro experiments performed on seven different prostate cell lines identified cells from the tumor microenvironment that secrete the highest levels of COL1A1. Expression of COL1A1 by these cells was confirmed by immunohistochemistry (IHC) using prostate tissue microarrays (TMA). In addition, protein array experiments identified elevated levels of several proteases in the urine of PCa patients, including MMP-9, uPA, ADAM-TS1 and several cathepsins. Substrate gel electrophoresis (zymography) revealed elevated activity of both MMP-9 and MMP-2 in urine from PCa patients. These data suggest that MMP-9 and MMP-2 may participate in the cleavage of collagen type 1, resulting in elevated levels of COL1A1 in urine of PCa patients. We are currently testing this hypothesis. In summary, COL1A1 may represent a novel non-invasive urinary biomarker that can effectively discriminate between BPH vs. localized PCa. (Supported by The Ellison Foundation)
Citation Format: Andrej Jedinak, Camille Vuichoud, Andrew El-Hayek, Katherine Kaplan, Jason Savage, Sarah Prophet, Adam S. Feldman, Kevin A. Camphausen, Kevin R. Loughlin, Marsha A. Moses. Mechanistic implications of COL1A1 as a prostate cancer biomarker [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 711. doi:10.1158/1538-7445.AM2017-711
Abstract 723: Improved detection of cancer specific serum exosomal aspartyl (asparaginyl) beta hydroxylase (HAAH)
Authors: Semenuk Mark A. , Cifuentes Anokhi S. , Ghanbari Eleanor R. , Lebowitz Michael S. , Ghanbari Hossein A. 
Published: July 2017

Abstract
By means of an ELISA, we have found the pan-cancer biomarker HAAH to be closely associated with serum exosomes primarily in cancers of the breast, lung, colon, and prostate. This new understanding of the HAAH target has led to a dramatically improved serological detection assay, and in turn diagnostic reagent kit. In keeping with the multivalent particulate nature of exosomes, appropriately reformatting the ELISA assay has yielded a simplified so-called simultaneous-homologous format. Currently in this format, a single monoclonal anti-HAAH antibody (FB50) serves both as microplate capture and as a biotinylated detector. All reagents, including peroxidase-streptavidin, are co-incubated in the FB50- coated microplate simultaneously with serum samples, in the absence of intervening sequential steps.
This considerably shorter exosome-enabled ELISA format requires half the time and yields generally on average a two-fold or higher increase in detection of HAAH. This format was evaluated with over 100 banked serum samples from several early stage cancers. While increasing the sensitivity for HAAH in cancer samples, the improved detection and performance has not caused any undesirable increases in false positives among more than 30 normal serum samples from healthy subjects. The reagent kit components include recombinant HAAH calibrators, positive /negative controls, vialed detection reagents and a Mylar packaged FB50 pre-coated microplate. The simplified reagent kit format has yielded close inter-operator and day to day trending consistency with a limit of detection (LOD) of 3 ng/mL.
Recognizing the exosomal nature of the HAAH target has resulted in some changes in blood sample procurement, sample processing, and sample shipping. Such field testing of the HAAH reagent kit was recently done with serum samples from 48 high risk or mildly symptomatic volunteers with general concerns about cancer. Upon testing these samples 9 had an HAAH level greater than 3.0 ng/ mL (range 4.2 to 116.7) and 39 had less than 3.0 ng/ mL. Based upon the post-analysis diagnostic determination, there were two false negatives and one false positive, hence an overall accuracy of 93.8%.
Citation Format: Mark A. Semenuk, Anokhi S. Cifuentes, Eleanor R. Ghanbari, Michael S. Lebowitz, Hossein A. Ghanbari. Improved detection of cancer specific serum exosomal aspartyl (asparaginyl) beta hydroxylase (HAAH) [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 723. doi:10.1158/1538-7445.AM2017-723
Abstract 730: High sensitive detecting procedure of circulating repetitive RNA as novel early marker of pancreatic cancer
Authors: Kishikawa Takahiro , Otsuka Motoyuki , Koike Kazuhiko 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (Pdac) is one of the most intractable malignancies due to difficulties in early detection. Although promising biomarkers are increasingly reported, such methods are not yet easy to apply clinically, mainly due to their low reproducibility or technical difficulties. In this study, we developed a convenient and sensitive method for quantifying aberrantly expressed satellite repeat RNAs in sera, which can be used to efficiently detect patients with Pdac. It is difficult to correctly quantitate repeat arrays because its repetitive nature makes it difficult to establish appropriate primers that amplify a single product using simple PCR procedures. Here, we introduce a Tandem Repeat Amplification by nuclease Protection (TRAP) method combined with droplet digital PCR (ddPCR) to detect human satellite II (HSATII) RNAs, which are specifically expressed in human Pdacs at greater levels than normal tissues. HSATII RNA core sequence levels in sera were significantly higher in Pdac patients compared with non-cancer patients (median copy number: 14.75 and 3.17 per µl in the training set and 17.35 and 2.9 in the validation set, respectively). In addition, patients with intraductal papillary mucinous neoplasm (IPMN), a precancerous lesion of Pdac, could also be efficiently detected. This method can be routinely applied to screen patients with Pdac and high-risk patients, facilitating the development of preventive medicine for this disease.
Citation Format: Takahiro Kishikawa, Motoyuki Otsuka, Kazuhiko Koike. High sensitive detecting procedure of circulating repetitive RNA as novel early marker of pancreatic 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 730. doi:10.1158/1538-7445.AM2017-730