bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1627: Custom VariantFlex technology allows rapid design and testing of reference materials for tumor genotyping assays
Authors: Huang Catherine , Santhanam Ram , Brudzewsky Dan , Brown Trevor , Garlick Russell , Anekella Bharathi 
Published: August 2018

Abstract
Introduction: Development and validation of tumor genotyping assays requires highly characterized reference materials for effective assessment of accuracy, precision, reproducibility and limits of detection. Highly multiplexed reference materials can facilitate and expedite these studies; however, there is not a single reference material that is appropriate for all assays. Traditional cancer cell line methods or genetic engineering methods can take 6 - 9 months, so more flexible solutions for reference materials are needed. Here we describe the development of VariantFlex technology, which enables a laboratory to configure a reference material to contain the variants of interest at the allele frequency of relevance to their studies in rapid time. Methods: A library of biosynthetic constructs was generated that contains ~140 somatic cancer DNA variants (SNVs, small and large indels and tandem duplications), ~27 RNA fusions, and 6 very large gene region constructs for copy number gains. TaqMan® digital PCR assays were developed to precisely quantify the variant allele fraction, fusion RNA concentration or copy number gain. As an example, biosynthetic constructs bearing multiple SNVs in TP53, PIK3CA and EGFR, large deletions in EGFR, and the structural variants NCOA4-RET and TPR-ALK, were selected from the VariantFlex library and spiked into DNA extracted from the highly characterized GM24385 cell line. The mixture was processed to obtain ctDNA-like profile, encapsulated to provide stability, and then diluted in artificial plasma to generate a customized reference material for liquid biopsy. Results: The ctDNA reference material was quantified by digital PCR and performance was verified on hybrid capture and amplicon based NGS assays. Variant allele frequency as low as 0.125% VAF was accurately targeted (range for 0.125% target was +/- 0.025% by digital PCR). The VariantFlex technology has been validated to work with amplified NGS workflows, hybrid-capture based NGS assays as well as non-NGS assays such as qPCR and array based methods. Conclusions: This study shows how a large library of cancer-related variants can facilitate rapid production of customized reference materials. The flexibility to include exactly the variants of interest, at the critical allele frequencies, and in the most patient-like format will facilitate assay development and validation.
Citation Format: Catherine Huang, Ram Santhanam, Dan Brudzewsky, Trevor Brown, Russell Garlick, Bharathi Anekella. Custom VariantFlex technology allows rapid design and testing of reference materials for tumor genotyping assays [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 1627.
Abstract 164: Ston2 knockdown promotes stem-like properties via dnmt1-mediated muc1 upregulation in ovarian cancer
Authors: Xu Shanshan 
Published: August 2018

Abstract
Cancer stem cells possess the ability of self-renewal, unlimited proliferation,and non-sensitivity to physical and chemical factors, which is regarded to be a cause of ovarian cancer recurrence, but the mechanism is currently unclear. We found that the expression of STON2 was significantly lower in ovarian cancer-stem like cells by LC-MS/MS-based label free quantitative proteomics approach and western blot validation. STON2 knockdown upregulated the expression of the CSC-related markers in protein level, increased the spheroids number and CD44+CD24−proportion. Besides, in vivo xenograft experiments, the volume of tumors from the shSton2 group were much bigger compared with the shNC group. Moreover, STON2 overexpression decreased the CSC-related markers and inhibited the spheroids number compared with the control group. Transcriptome sequencing data showed that MUC1 is negative correlation with STON2, which were verificated by RT-PCR and western blot analysis. Subsequently, we found that MUC1 mediated the role of STON2 in regulation of stem-like properties in ovarian cancer. MUC1 knockdown resulted in a significant decrease in the sphere-forming ability, CSC-related markers and CD44+CD24−proportion. In addition, MUC1 overexpression caused an increment of CSC-related markers expression and CD44+CD24−proportion. Furthermore, we found that the reducing of sphere-forming ability caused by STON2 overexpression was rescued by MUC1 overexpression. As MUC1 can be regulated through epigenetic mechanisms, we found that DNA methylation inhibitor Azacitidine was able to rescue the upregulation of MUC1 by STON2. The DNA methylation levels of MUC1 in one CpG-rich region were then evaluated with pyrosequencing, and the data displayed that the siSton2 group is lower than the control group. Furthermore, we found that the DNMT1 as a member of the DNA methyltransferase family decreased following with STON2 knockdown in protein level, rather than in mRNA level. We thus knock down DNMT1 using specific siRNA, and found that MUC1 overexpression both in mRNA level and protein level. In this study, we focused primarily on STON2 repression leading to DNMT1 downregulation and MUC1 activation is a main mechanism underlying the maintenance of stem-like properties in ovarian cancer.
Citation Format: Shanshan Xu. Ston2 knockdown promotes stem-like properties via dnmt1-mediated muc1 upregulation in ovarian 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 164.
Abstract 1645: Innovative discovery of therapeutic plateletpheresis in patients with thrombocytosis using the Fresenius COM.TEC
Authors: Jin Yanxia , Yuan Guolin , Zhou Fuling 
Published: August 2018

Abstract
Plateletpheresis is an important therapeutic method for treatment of patients with myeloproliferative neoplasms (MPN) presenting with thrombocytosis. This study analysed the collection efficiency of plateletpheresis (CEPP) for 94 patients with thrombocytosis who underwent plateletpheresis by Fresenius COM.TEC machine, especially analysed the CEPP for enrolled patients with PLT count at 500-1000 × 109/l. The results indicated that this device could significantly decreased PLT count, and with mean CEPP of 24.23±17.42% that ranges from 3.18% to 78.46%. Further analysis shows that the PLT counts were 500-800 × 109/l for patients, which CEPP was above 42.1% with a lower pooled WBC and RBC. Paired t-test suggested that the red blood cell (RBC) counts, PLT counts, white blood cell (WBC) counts, monocyte counts and haematocrit (HCT) significantly decreased after plateletpheresis. Bivariate correlation and multiple logistic regression analysis showed that PLT count groups, hemoglobin (HGB) before apheresis were greatly correlated with CEPP. We suggest that the device is effective at reducing platelet counts with acceptable efficiency and it is available for plateletpheresis when the PLT counts about 500-800 × 109/l for patients with higher HGB pre-apheresis in female patients.
Citation Format: Yanxia Jin, Guolin Yuan, Fuling Zhou. Innovative discovery of therapeutic plateletpheresis in patients with thrombocytosis using the Fresenius COM.TEC [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 1645.
Abstract 1653: Design and synthesis of basic amino selective estrogen receptor degraders (BA-SERDs) for treatment-resistant breast cancer
Authors: Lu Yunlong , Thatcher Gregory R. 
Published: August 2018

Abstract
About 1 in 8 United States women (about 12%) will develop invasive breast cancer during their lifespan. Approximately 40,000 women are expected to die from breast cancer each year. The largest single breast cancer subtype is defined as estrogen receptor alpha (ERα; ESR1) positive breast cancer (75%), wherein ERα played a critical role in cancer cell survival, proliferation and metastasis. The dysregulation of ER signaling formed the most important molecular event in the ER positive (ER+) breast cancer. Endocrine therapy (ET) had been successfully employed on such breast cancer patients and most of them had substantial reduced risks of breast cancer recurrence and mortality in the initial 5-10 years. However, the development of resistance to ET has the greatest impact on clinical use. The emergence of resistance is inevitable over time and will eventually become metastatic disease after long term of ET. Recent studies confirmed treatment failure of SERMs and AIs in ER+ metastatic settings, whereas ERα remains engaged in the advanced disease and contributes to disease pathogenesis. Fortunately, the treatment resistant breast cancer patients remain responsive to fulvestrant (ICI182,780) which has been described as a “pure antagonist” and caused ERα degradation as a SERD. Nonetheless, the pharmaceutical liabilities of fulvestrant including poor solubility and pharmacokinetics (PK) resulted in poor compliance. The clinical development of orally bioavailable SERDs i.e. GDC-0810, AZD9496, RAD1901 is needed to overcome these shortcomings. Herein, our lab identified a novel class of BA-SERDs to circumvent drug resistance.
Citation Format: Yunlong Lu, Gregory R. Thatcher. Design and synthesis of basic amino selective estrogen receptor degraders (BA-SERDs) for treatment-resistant 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 1653.
Abstract 1661: Discovery of potent Abelson kinase inhibitors from the scaffold of pyrano[2,3-d]pyrimidin-7-one
Authors: Wu Zhixing , Fu Boqiao , Qiao Changjiang , Nagaraju Ashila , Lu Dai 
Published: August 2018

Abstract
Tyrosine kinases regulate cell proliferation, survival, invasion and angiogenesis during tumor initiation and progression. The Abelson (ABL) family of protein kinases comprises ABL1 and ABL2, which link diverse extracellular stimuli to signaling pathways that control cell growth, survival, invasion, adhesion and migration. Inhibition of ABLs has been implied in many type of hematopoietic malignancies and solid tumors. The compound PD173955 is a potent ABL kinase inhibitor. It was developed from the scaffold pyrido[2,3-d]pyrimidin-7-one by Parke-Davis (Pfizer). To discover novel ABL inhibitors, we investigated the scaffold pyrano[2,3-d]pyrimidin-7-one, which is structurally analogous to pyrido[2,3-d]pyrimidin-7-one. This novel scaffold has not been extensively studied in synthetic chemistry and pharmacology. The compound LDK1504 generated from this scaffold is a close analog of PD173955. It was synthesized as a prototypical compound from the pyrano[2,3-d]pyrimidin-7-one scaffold. In the enzymatic assays, LDK1504 was demonstrated with an inhibitory activity comparable to PD173955 for ABL1 kinase. It can inhibit the ABL1 kinase with an IC50 of 18.7 nM. Further optimization leads to the identification of LDK1512 (Kd = 0.38 nM; IC50 = 1.27 nM) against ABL1. The preparation of this class of compounds was achieved through a facile synthesis of 6-bromo-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one followed by Suzuki coupling reaction and derivatization of the C-2 position of the pyrimidine ring. In this presentation, our synthesis, preliminary SAR of this class of compounds, and kinase selectivity profiling will be discussed.
Citation Format: Zhixing Wu, Boqiao Fu, Changjiang Qiao, Ashila Nagaraju, Dai Lu. Discovery of potent Abelson kinase inhibitors from the scaffold of pyrano[2,3-d]pyrimidin-7-one [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 1661.
Abstract 1666: Novel glucose transporter inhibitors decrease glioblastoma growth and glucose uptake
Authors: Libby Catherine J. , Zhang Sixue , Benavides Gloria A. , Li Yanjie , Redmann Matthew , Tran Anh N. , Otamias Arphaxad , Darley-Usmar Victor , Napierala Marek , Zhang Jianhua , Zhang Wei , Hjelmeland Anita 
Published: August 2018

Abstract
Glioblastoma multiform (GBM) is the most common primary malignant adult brain tumor and one of the deadliest cancers. Patients with GBM typically undergo surgical resection, radiation and chemotherapy with temozolomide. Complete tumor resection is virtually impossible due to tumor location and the highly infiltrative nature of GBM, which leads to disease recurrence near the original tumor site. As such, these patients have a dramatically decreased life expectancy. Therapeutic development to prolong survival has been hampered by a high degree of inter- and intra-tumoral heterogeneity. Contributing to tumor heterogeneity is a subset of highly tumorigenic cells, termed brain tumor initiating cells (BTICs), that are able to self-renew and can be highly invasive and therapy resistant. BTICs are often enriched in perinecrotic regions, a GBM hallmark, where they can survive under nutrient restriction via increased glucose transporter 3 expression (GLUT3). GLUT3 has a 5-fold greater capacity for glucose transport than the other major glucose transporter isoform in the brain, GLUT1, and is typically restricted to neurons, testis, preimplantation embryos, and stem cells. GLUT3 expression is elevated in many solid tumor types, including GBM, and correlates with poor patient prognosis. Previously, we have shown that knockdown of GLUT3 in BTICs significantly inhibits their growth both in vitro and in vivo, indicating GLUT3 is a possible target for therapeutic intervention. Using structure based virtual screening, we have identified novel GLUT inhibitors that preferentially decrease the growth and glucose uptake of BTICs with minimal toxicity to non-malignant cells in vitro. Preliminary in vivo assessment of these compounds has not indicated toxicity. Our goal is to identify a potential new therapeutic option targeting metabolic reprogramming for the treatment of glioblastoma, as well as other tumor types.
Citation Format: Catherine J. Libby, Sixue Zhang, Gloria A. Benavides, Yanjie Li, Matthew Redmann, Anh N. Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Wei Zhang, Anita Hjelmeland. Novel glucose transporter inhibitors decrease glioblastoma growth and glucose uptake [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 1666.
Abstract 1670: Discovery of novel water-soluble derivatives of mebendazole as selective CLK1/4 kinase inhibitors and their anticancer cancer activity
Authors: Sun Lijun , Cheong Jae Eun , Zaffagni Michela , Zhou Kun , Zetter Bruce 
Published: August 2018

Abstract
Metastatic cancers remain clinically challenging and account for more than 90% of all cancer deaths. Drugs used to treat advanced metastatic cancers often generate drug resistance and relapse. Therefore, there is a critical need for novel therapeutic approaches for patients with advanced stage cancers that do not respond to any currently available anticancer therapies. Mebendazole and structurally related benzimidazole analogues, which are FDA approved compounds used to treat helminthic infections in the gastrointestinal track, are effective in inhibiting in vitro cancer cell proliferation. Unfortunately, their therapeutic applications in metastatic cancer are limited by their extremely low solubility and poor bioavailability. Further, the mechanism of the anticancer activities of this class of compounds is poorly defined. Here, we report the design and synthesis of water-soluble benzimidazoles as novel anticancer agents. Among them, the novel oxetanyl substituted compound, OBD9 (Methyl (5-(4-(methyl(oxetan-3-yl)amino)benzoyl)-1H-benzo[d]imidazol-2-yl)carbamate), demonstrated potent cytotoxicity towards a variety of highly aggressive cancer lines including prostate, lung, and ovarian cancers (IC50: 0.9-3.8 μM). In the NCI60 cancer cell panel screen, OBD9 broadly inhibited the proliferation of leukemia, melanoma, and breast and colon cancers. The aqueous solubility of OBD9 achieved 361 μM vs &lt;1μM for mebendazole. In a mouse xenograft model of the highly metastatic human prostate cancer PC3MLN4, OBD9 (30 mg/kg/day, three times/week for two weeks) significantly inhibited the growth of established tumors (treatment-to-control ratio: 0.36) without noticeable toxicity. We performed broad kinase screening (KINOMEscan, DiscoverX) to explore the mechanism of action and discovered OBD9 as a potent and highly selective inhibitor of Cdc-like kinase 1 and 4 (CLK1 and 4). The Selectivity Score of OBD9 at 10 μM concentration in the 403 non-mutant kinases is 0.002; and its IC50 is 1.5 and 1.2 μM for CLK1 and CLK4, respectively. CLKs are nuclear serine/threonine (S/T) kinases that regulate gene splicing and are frequently over activated in cancers. Our results suggest that OBD9 impedes cancer growth at least in part by inhibiting CLK1/4.
Citation Format: Lijun Sun, Jae Eun Cheong, Michela Zaffagni, Kun Zhou, Bruce Zetter. Discovery of novel water-soluble derivatives of mebendazole as selective CLK1/4 kinase inhibitors and their anticancer cancer 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 1670.
Abstract 169: Identification of RNA aptamers selectively recognizing and affecting glioblastoma stem cells
Authors: Affinito Alessandra , Quintavalle Cristina , Albero Maurizio , Vilardo Claudia , Palma Francesco , Roscigno Giuseppina , Vitiani Lucia Ricci , Pallini Roberto , Esposito Carla Lucia , Franciscis Vittorio de , Condorelli Gerolama 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumour in adults. Despite advances in surgical and medical neuro oncology, prognosis for GBM patients remains dismal, with a median survival of about 15 months. It has been demonstrated that the modest benefit of conventional therapies depends on a small population of cancer stem cells within the tumor, named Glioma Stem Cells (GSCs) that cause tumor relapse and chemoresistance and therefore could play a key role in GBM recurrence. Thus, the identification of new specific ligands for GSCs could be a fundamental challenge for the development of effective glioma therapies. Here, we developed an in vitro evolution based approach, named differential whole cellSELEX; it is used to generate nucleic acid ligands, named aptamers, with high affinity and specificity for GSCs. Aptamers, were obtained through the iterative evolution of a random pool of sequences using human primary GSCs as target. Among different potential candidates we focused on one sequence, named 40L. The 40L aptamer and its truncated form, 40S, were selective for human GSCs distinguishing them from tumor differentiated cells, obtained from the stem cells induced to differentiate. 40L revealed to be functionally active on target cells and able to inhibit stemness, cell growth and migration. 40s preserves binding ability of 40L sequence and it has further proven to strongly reduce tumor proliferation in in vivo experiment. Moreover, both 40L and 40s were able to rapidly internalize upon target binding and therefore may serve as selective vehicle for therapeutics.In conclusion, our results indicate that 40L and its short form 40s can selectively target GSCs both in vitro and in vivo. Given the crucial role of these cells in GBM recurrence and therapy resistance, 40L and 40s represent innovative drug candidates with a great potential in the GBM treatment.
Citation Format: Alessandra Affinito, Cristina Quintavalle, Maurizio Albero, Claudia Vilardo, Francesco Palma, Giuseppina Roscigno, Lucia Ricci Vitiani, Roberto Pallini, Carla Lucia Esposito, Vittorio de Franciscis, Gerolama Condorelli. Identification of RNA aptamers selectively recognizing and affecting glioblastoma stem cells [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 169.
Abstract 1692: The impact of neutrophil/lymphocyte ratio as the predictive marker to anti-PD-1 antibody treatment in NSCLC patients
Authors: Tanimura Keiko , Yamada Tadaaki , Tamiya Nobuyo , Kaneko Yoshiko , Takeda Takayuki , Uchino Junji , Kubota Yutaka , Takayama Koichi 
Published: August 2018

Abstract
Background: Anti-Programmed death 1 (PD-1) antibody which enhances anti-tumor activity of cytotoxic-T-lymphocytes by blockade of PD-1/PD-L1 pathway has demonstrated improvement of survival in the patients with advanced non-small-cell lung cancer (NSCLC). PD-1 and its ligand PD-L1 is also known as key players in the formation of tumor microenvironment, closely related with inflammatory cytokines. Here, we retrospectively analyzed the peripheral blood cells as a surrogate marker for predicting outcome of immune checkpoint inhibitors (ICI). Method: Total of 78 cases treated with anti-PD-1 antibodies, nivolumab or pembrolizumab from February 2016 to September 2017 were registered retrospectively. We investigated the differential leukocyte counts, C-reactive protein (CRP) and other peripheral blood parameter on the treatment progress with ICI, and evaluated correlation between response to ICI and peripheral blood cells. Result: Out of 78 cases, 56 cases (77%) were treated with nivolumab, 18 cases (23%) were treated with pembrolizumab, and 4 cases (5%) have treatment history of both agents. Median follow up period was 5.7 months (range: 0.4-18.7 months). Median progression free survival (PFS) and median overall survival (OS) were 2.4 and 8.7 months, respectively. Overall response rate was 21.8%. Of some parameters in peripheral blood cells, higher absolute neutrophil count (ANC), CRP at baseline were associated with shorter OS. Furthermore, we determined neutrophil / lymphocyte ratio (NLR), platelet / lymphocyte ratio (PLR), lymphocyte / monocyte ratio (LMR) and prognostic nutritional index (PNI), which were known as predictive biomarkers in various tumor type. In patients with longer PFS for ICI treatment, ANC, NLR and CRP remained low level until disease progression, whereas these markers increased during ICI treatment in the patients with shorter PFS for ICI. Conclusion: Our retrospective analysis showed that ANC, NLR and CRP may predict response and acquisition of resistance to anti-PD-1 therapy in NSCLC patients. These results suggest that peripheral blood findings might be promising as a predictive biomarker of ICI treatment.
Citation Format: Keiko Tanimura, Tadaaki Yamada, Nobuyo Tamiya, Yoshiko Kaneko, Takayuki Takeda, Junji Uchino, Yutaka Kubota, Koichi Takayama. The impact of neutrophil/lymphocyte ratio as the predictive marker to anti-PD-1 antibody treatment in NSCLC 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 1692.