bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3612: Elevated TGFa levels in chronic mylogenous leukemia (CML) patient plasma measured by a highly sensitive single molecule array immunoassay
Authors: Chenna Ahmed , Cai Li , Petropoulos Christos , Winslow John W. 
Published: August 2018

Abstract
Introduction: Recent reports suggest that cytokine and growth factor profiling are prognostic in myelodisplasias and CML. TGF-α and IL-6 plasma levels selectively identified CML patients failing to achieve an early molecular response (EMR), or progressed on imatinib therapy (Nievergall et al, 2016). In patients failing to achieve EMR, the median TGFα concentrations were in the low pg/mL range while IL-6 levels were sub-pg/mL or undetectable. Thus, to accurately and reproducibly measure TGFα and IL-6 levels in blood as prognostic or predictive markers of imatinib response, there is a need for highly sensitive immunoassays. Here we demonstrate the utility of using a digital immunoassay to measure sub-pg/mL levels of TGFα and IL-6 in CML plasma samples assessed for BCR-ABL fusion transcripts.
Methods: Single molecule array immunoassays (Simoa) for TGFα and IL-6 were performed on the HD-1 platform (Quanterix), qualified based on precision, reproducibility, linearity, sensitivity according to kit specifications. CML blood samples were obtained from CMBP, LabCorp, Inc, following BCR-ABL e1b2, b2b2, and b3b2 transcript fusion testing by RT-PCR.
Results: TGFα and IL-6 concentrations in the plasma of 77 CML patients were determined and compared to levels in healthy controls. TGFα in CML plasma was elevated and ranged ~20-fold (6.13-118.6 pg/mL), in contrast to the low levels and narrow range in healthy controls (range = 1.11-3.17 pg/mL). Median TGFα levels were 10-fold higher in CML patient plasma (median = 18.8 pg/mL) relative to healthy controls (median = 1.8 pg/mL; p &lt;0.0001). IL-6 levels ranged broadly in CML plasma (0.12-12.6 pg/mL) relative to healthy controls (0.3-1.04pg/mL), though median levels were not significantly different (CML = 0.61 vs 0.69, p = 0.873). TGFα and IL-6 concentrations were not significantly correlated. TGFα levels appear elevated in CML samples expressing all 3 BCR-ABL transcripts, however, a larger number of samples enriched in fusion transcripts are being assessed to confirm possible correlations.
Conclusions: We have qualified novel highly sensitive single molecule array immunoassays to measure TGFα and IL-6 in the plasma of CML patients and healthy controls, and found significantly elevated levels of TGFα in CML plasma. These results support further investigation of TGFα and IL-6, using sensitive immunoassays, as potential prognostic and predictive markers of CML disease progression and treatment outcome.
Citation Format: Ahmed Chenna, Li Cai, Christos Petropoulos, John W. Winslow. Elevated TGFa levels in chronic mylogenous leukemia (CML) patient plasma measured by a highly sensitive single molecule array immunoassay [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 3612.
Abstract 3625: MET signaling upregulates PD-L1 expression in human lung and gastric cancer
Authors: Ahn Hyunkyung , Kim Sehui , Jang Ji Young , Kwon Dohee , Koh Jaemoon , Kim Young A , Chung Doo Hyung , Jeon Yoon Kyung 
Published: August 2018

Abstract
Background: Tyrosine kinase receptor, MET, plays an important role for the progression of tumor through diverse mechanisms. Cancer immunotherapy targeting PD-1/PD-L1 pathway shows clinical benefit in patient with PD-L1 expressing solid tumor. In our previous study on non-small cell lung cancer (NSCLC) using immunohistochemistry, MET overexpression was significantly associated with programmed cell death-ligand 1 (PD-L1) overexpression. Thus, we investigated if MET signaling pathway is involved in PD-L1 expression in tumor cells.
Method and Result: Lung adenocarcinoma cell lines including H596 (harboring MET exon 14 skipping mutation), H1993 (harboring MET gene amplification), H23 and H522 (MET wild-type), and a gastric carcinoma cell line, Hs746T (harboring MET exon 14 skipping mutation and gene amplification) were used. Hs746T cells were treated with MET inhibitor or transfected with MET siRNA and subject to microarray analysis. MET inhibition or knockdown led to changes in expression level of variable immune-related molecules, of which PD-L1 was one of the most down-regulated molecules. Stimulation of H596, H23 and H522 cells with HGF, a MET ligand, increased PD-L1 expression at the mRNA and protein level. Treatment of H1993 and Hs746T cells with MET inhibitor or MET knockdown using siRNA resulted in down-regulation of PD-L1 at the mRNA, total protein, and surface expression levels. PI3K/Akt and MAPK/Erk signaling pathways were involved in MET-mediated PD-L1 up-regulation in H1993 and Hs746T cells. Finally, the Cancer Genome Atlas (TCGA) analysis showed that MET and PD-L1 expression are significantly positively correlates with each other in patients with lung cancer (in NSCLC, rho=0.219 [p&lt;0.001]; in adenocarcinoma, r=0.401 [p&lt;0.001]; in squamous cell carcinoma, r=0.144 [p=0.001]) and in patients with gastric cancer (r=0.137 [p=0.005]).
Conclusion: This study demonstrates that MET signaling increases PD-L1 transcription and protein overexpression in lung and gastric cancer cells, which might contribute to immune escape of tumor via PD-1/PD-L1 pathway. MET-targeted therapy may be considered as combination therapy with PD-1/PD-L1 blockades.
Citation Format: Hyunkyung Ahn, Sehui Kim, Ji Young Jang, Dohee Kwon, Jaemoon Koh, Young A Kim, Doo Hyung Chung, Yoon Kyung Jeon. MET signaling upregulates PD-L1 expression in human lung and gastric 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 3625.
Abstract 3630: Deep and durable response with dual anti-CTLA-4 and PD-1 blockade in mismatch repair (MMR) proficient endometrial cancer
Authors: Oh Michael S. , Chae Young 
Published: August 2018

Abstract
Immune checkpoint inhibitors have shown promising efficacy in multiple cancer types, but have yet to be extensively validated in endometrial cancer. However, the recent FDA approval of PD-1 inhibitors for mismatch repair (MMR) deficient tumors has extended use of these treatments to all cancer types. PD-L1 positivity in tumor tissue has also been shown to predict susceptibility to immunotherapy and has been used to guide use of these treatments. Despite these advances, the response to immunotherapy in endometrial cancer remains poorly understood. Here, we describe the case of a patient with MMR proficient, PD-L1-negative stage IV endometrial cancer with positive response to combination PD-1 and CTLA-4 inhibition. The patient initially presented with ascites and elevated tumor markers, and cytology from peritoneal fluid showed endometrial adenocarcinoma with squamous and mucinous differentiation and clear cell features. She underwent surgical debulking with both neoadjuvant and adjuvant cycles of docetaxel and carboplatin, but unfortunately had progressive metastatic disease within 4 months. The patient declined further chemotherapeutic agents, and thus was instead trialed on combination nivolumab and ipilimumab despite her cancer exhibiting MMR proficiency and negative PD-L1. She demonstrated deep and durable on-going partial response to this treatment that has persisted still after 10 months. Her course has notably been complicated by hypophysitis that manifested after 5 months of treatment as worsening fatigue, but she has been able to continue with her treatment regimen. This case indicates the potential existence of an endometrial cancer subtype that is sensitive to immune checkpoint blockade, but based on mechanisms other than those driven by MMR deficiency or PD-L1 positivity. Improved understanding of immunotherapy in advanced endometrial cancer is clearly needed and offers the potential to significantly enhance patient outcomes.
Citation Format: Michael S. Oh, Young Chae. Deep and durable response with dual anti-CTLA-4 and PD-1 blockade in mismatch repair (MMR) proficient endometrial 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 3630.
Abstract 3660: Can the presence of fusion genes in circulating cell-free DNA serve as potential biomarkers for Ewing's sarcoma
Authors: Iwata Shintaro , Kageyama Hajime , Yonemoto Tsukasa , Itami Makiko 
Published: August 2018

Abstract
Background: Circulating cell-free DNA (cfDNA) is fragmented DNA derived from tumors that circulates in the blood of patients. With liquid biopsy, cfDNA has the potential to be used to monitor tumor burden in real time. Most reports have described that tumor-specific alterations in cfDNA are mutations, although little has been reported for the detection of tumor specific gene fusions. The objective of this study was to identify whether cfDNA can be used to detect tumor specific gene fusions and whether this would reflect the tumor burden of patients with Ewing's sarcoma.
Patients and Methods: Multiplex long-range genomic PCR was performed to detect patient-specific genomic breakpoints in eight patients. Probes for digital PCR were designed based on the genomic breakpoint of each patient. cfDNA was extracted from the serum of patients, which was drawn at multiple time-points (pretreatment, completion of the treatment, and/or relapse). cfDNA quantification was performed by digital PCR (BioRad Qx-200).
Results: Gene fusions in the cfDNA were detected in six (75%) of eight patients with high specificity. The relative gene fusion copy ratio (gene fusion copy number/wild KRAS copy number) was higher in the patients with M1b (extrapulmonary metastases at diagnosis) compared to the patients with M1a (pulmonary metastases at diagnosis) or M0 (no metastasis), although no significant relationship was observed between the relative gene fusion copy ratio and chemosensitivity. In each patient, the relative gene fusion copy ratio was the highest in pretreatment samples and decreased as the treatment progressed. Patients with relapse displayed an elevated relative gene fusion copy ratio in advance of clinical manifestation or elevation of lactase dehydrogenase.
Conclusion: The amount of cfDNA in the serum strongly correlated with the treatment stage and would be useful as an early biomarker for Ewing's sarcoma patients.
Citation Format: Shintaro Iwata, Hajime Kageyama, Tsukasa Yonemoto, Makiko Itami. Can the presence of fusion genes in circulating cell-free DNA serve as potential biomarkers for Ewing's sarcoma [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 3660.
Abstract 3661: Comparison of ctDNA markers in matched urine and plasma from patients with liver cancer
Authors: Lee Tai-Jung , Jain Surbhi , Steffen Jamin D. , Zhang Adam M. , Hu Chi-Tan , Hamilton James P. , Su Ying-Hsiu 
Published: August 2018

Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer worldwide and a leading cause of global cancer mortality. Lack of efficient early detection and limited therapeutic options are two key contributing factors for the dismal prognosis of this disease. We have previously shown that urine contains fragmented, circulation-derived cell-free DNA that can be used for detection of circulating tumor DNA (ctDNA) if a tumor is present, suggesting urine as an alternative body fluid to plasma for cancer liquid biopsy. This study compared the detectability of five known HCC-associated DNA modifications, including genetic mutations (TERT -124 G&gt;A, TP53 249 G&gt;T and CTNNB1 hotspot at codon 32-45) and epigenetic methylation (mGSTP1, mRASSF1A), in matched urine and plasma from patients with liver cancer. In order to increase the sensitivity of detecting DNA modifications from the short, fragmented DNA templates, specialized short amplicon PCR assays were developed. To compare the detectability of HCC ctDNA markers in urine and plasma, 26 pairs of urine and plasma samples from HCC patients were identified and tested for five HCC ctDNA markers. In this cohort, 17 of 26 (65%) HCC samples had serum AFP above 20 ng/mL and were considered AFP-positive HCC. By using our HCC DNA biomarker panel composed of 5 assays, 22/26 (84.6%) urine and 23/26 (88.5%) plasma samples were found to have at least one DNA marker detected. In the combination of our HCC DNA biomarker panel with serum-AFP, the sensitivity of HCC detection in a liquid biopsy of urine and plasma as compared to serum-AFP alone (the current most used screening marker) increased from 65% to 92.3% for both urine plus AFP and plasma plus AFP. Further studies to include non-HCC samples (such as cirrhosis) to determine the specificity of the HCC DNA biomarker panel for liquid biopsy are in progress. In conclusion, our research provides the promising potential for HCC liquid biopsy screening in at-risk populations and precision medicine by using plasma, urine, or both as body fluids.
Citation Format: Tai-Jung Lee, Surbhi Jain, Jamin D. Steffen, Adam M. Zhang, Chi-Tan Hu, James P. Hamilton, Ying-Hsiu Su. Comparison of ctDNA markers in matched urine and plasma from patients with liver 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 3661.
Abstract 367: Methods to enhance the optical resolution for 3D-SIM for the study of Hodgkin's lymphoma nuclei
Authors: Szczurek Aleksander T. , Contu Fabio , Vanni Roberta , Knecht Hans , Johnson Nathalie , Haliotis Tina , Mai Sabine 
Published: August 2018

Abstract
In spite of a great deal of knowledge already available, the precise higher order organization of chromatin is still a subject of an debate. Moreover, cancerous cells have an altered chromatin organization in comparison to their healthy counterparts. This is also the case for Hodgkin's lymphoma (HL) - a lymphoid malignancy of B cell origin. HL comprises two cell types, the Hodgkin cells and the diagnostic bi- or multinucleated Reed-Sternberg (RS) cells readily distinguishable from healthy lymphocytes. Patient stratitifcation has been proposed through the quantitative analysis of 3D nuclear telomere organization. With the advent of super resolution microscopy (SRM), further insights into the spatial organization of the cancer genome become feasible. This includes the study of chromatin arrangement with SRM. However, its application to HL remains limited due to technical difficulties: HL cells display thickness of &gt;10µm resulting in light scattering and decreased signal-to-noise ratio.
Structured Illumination Microscopy (SIM, a SRM type) in particular has advanced studies of the sub-cellular structures. It relies on projection of excitation pattern on to a fluorescently labeled sample. Sample's information is then shifted to a detectable band doubling the 3D resolution. Sample's refractive index homogeneity and counteracting photo-bleaching are both crucial for maintenance of the sharp illumination pattern and high-quality SIM, particularly in thick samples. Nevertheless, sample mounting media for SIM have not undergone a significant evolution since almost a decade.
By identification and systematic comparison of non-hazardous components of mounting media we demonstrate increased sample's transparency and consequently improved SIM-quality. Using these novel sample clearing protocols we demonstrate high-resolution chromatin organization at ~120nm level in large RS cells of HL cell lines and in patient samples compared to lymphocytes. This work is of relevance of identification of new diagnostic structural biomarkers for HL.
Citation Format: Aleksander T. Szczurek, Fabio Contu, Roberta Vanni, Hans Knecht, Nathalie Johnson, Tina Haliotis, Sabine Mai. Methods to enhance the optical resolution for 3D-SIM for the study of Hodgkin's lymphoma nuclei [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 367.
Abstract 3687: Dot1l inhibition selectively impairs androgen receptor dependent prostate cancer growth through loss of telomere integrity
Authors: Vatapalli Rajita , Rodriguez Yara , Zhao Changsheng , Sagar Vinay , Anker Jonathan , Pamarthi Sahithi , Unno Kenji , Carneiro Benedito , Chakravarti Debabrata , Abdulkadir Sarki 
Published: August 2018

Abstract
The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and this histone mark is associated with activation of gene expression. DOT1L has a well-known role in MLL fusion leukemogenesis, however, its role in prostate cancer is yet to be elucidated. Here we show that DOT1L is overexpressed in many solid tumors including prostate cancer and is associated with a poor outcome. Genetic and chemical targeting of DOT1L showed a preferential loss in cell viability and colony formation in androgen receptor (AR)-signaling competent prostate cancer cells, including castration-resistant and enzalutamide-resistant cells. DOT1L inhibition reduced AR levels and upregulated enzymes involved in testosterone catabolism but only affected the expression of a subset of AR target genes. More importantly, loss of DOT1L selectively impaired telomere integrity by promoting telomere uncapping and shortening in AR-signaling competent cells. DOT1L inhibition also reduced the expression of telomerase and Shelterin complex genes including TRF2 and POT1. Recruitment of AR to telomeres and K79 methylation at sub-telomeric regions was also diminished. Consequently, loss of DOT1L leads to induction of Telomere dysfunction induced foci (TIF) and activates a cellular senescence program in these cells. Hence, these results provide compelling evidence for DOT1L inhibition as a novel therapeutic approach in advanced prostate cancers.
Citation Format: Rajita Vatapalli, Yara Rodriguez, Changsheng Zhao, Vinay Sagar, Jonathan Anker, Sahithi Pamarthi, Kenji Unno, Benedito Carneiro, Debabrata Chakravarti, Sarki Abdulkadir. Dot1l inhibition selectively impairs androgen receptor dependent prostate cancer growth through loss of telomere integrity [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 3687.
Abstract 3688: A novel biomarker for pancreatic cancer, sTRA, and CA19-9 define separate subpopulations of PDAC cells with distinctions in behavior and molecular characteristics
Authors: Barnett Daniel , Liu Ying , Gao ChongFeng , Wisniewski Luke , Partyka Katie , Barry Anna , Hostetter Galen , Singhi Aatur , Brand Randall E. , Drake Richard R. , Haab Brian B. 
Published: August 2018

Abstract
Cancer cells in pancreatic ductal adenocarcinomas (PDACs) exhibit tremendous diversity in behavior and phenotype, but no biomarkers are available to identify subtypes with clinically significant differences in behavior. We recently identified a new marker of pancreatic cancer, called sTRA, that is expressed on cancer cells with different morphologies and molecular characteristics than cancer cells expressing the biomarker CA19-9. Here we tested the hypothesis that the two types of cells have differences between them in behavior, gene expression, and associations with outcome. In cell line models, sTRA-expressing cancer cells were more resistant to drugs, more invasive, and slower-growing than the CA19-9-expressing cells. Patient-derived xenograft tumors produced either CA19-9 or sTRA, and RNA-seq analysis revealed significant, nonrandom differences between the sTRA-expressing and CA19-9-expressing tumors. Each subpopulation was found in lymph nodes or livers with levels that significantly correlated with their matched primary tumors. In an analysis of two tissue microarrays covering 45 and 41 patients, the tumors containing high levels of sTRA-expressing cancer cells had the shortest survival times. These data support the existence of two distinct subtypes of PDAC cells, respectively marked by CA19-9 and sTRA. Together the markers could have value for predicting the behavior of tumors and for isolating, characterizing, and targeting specific subtypes of cancer cells.
Citation Format: Daniel Barnett, Ying Liu, ChongFeng Gao, Luke Wisniewski, Katie Partyka, Anna Barry, Galen Hostetter, Aatur Singhi, Randall E. Brand, Richard R. Drake, Brian B. Haab. A novel biomarker for pancreatic cancer, sTRA, and CA19-9 define separate subpopulations of PDAC cells with distinctions in behavior and molecular characteristics [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 3688.
Abstract 3711: Smart therapy: Using CCND1-targeted siRNA-loaded liposomes to sensitize mantle cell lymphoma cells to cisplatin
Authors: Gandhi Tanvi N. , Masamha Chioniso P. , Das Sudip K. , Das Nandita G. 
Published: August 2018

Abstract
Mantle cell lymphoma (MCL) is the most aggressive subtype of B-cell non-Hodgkin's lymphoma, due to its refractory nature and high relapse rate. It is characterized by the aberrant overexpression of the cell cycle regulatory oncogene, cyclin D1 (CCND1), which occurs as a result of a t (11; 14) chromosomal translocation event, the initiating lesion for MCL tumorigenesis. Current therapy includes a series of different chemotherapy regimens often involving a combination of at least four drugs, but there is no gold standard combination treatment regimen. One of the most commonly used drugs in combination treatment is the chemotherapeutic agent, cisplatin. High concentrations of cisplatin in the body cause nausea, vomiting, loss of taste and, more severely, nephrotoxicity. A commonly used approach to reduce the concentration of a chemotherapeutic agent is to use it in combination with a molecular targeting agent. Since cyclin D1 is overexpressed in MCL, we hypothesize that knocking down CCND1 by using siRNA will sensitize MCL cells to cisplatin. We developed CCND1 primers to detect reduction in CCND1 mRNA levels after RNAi using PCR. The greatest challenge against siRNA delivery is its poor stability in vivo and low efficacy of transfection into tumor cells. Our objective is to formulate a dosage form that could be practically adapted in a clinical setting in the future. We developed a liposome formulation that uses a balanced ratio of neutral and cationic lipids to serve as a carrier for the siRNA and improves delivery to tumor cells. Our CCND1 siRNA and control siRNA-loaded liposomes have an average particle size below 150 nm and an overall cationic charge less than 30V. These characteristics are important for the trafficking of the liposome carrier in vivo and its eventual uptake into tumor tissue. Fluorescence assays were used to detect and quantify the amounts of siRNA bound to the liposome. We determined the effect of the liposomes in combination with cisplatin on MCL cell viability using a colorimetric MTT assay. The novel CCND1 siRNA-loaded liposome combined with cisplatin was found to show a dose-dependent decrease in cell viability and was more potent than either CCND1 siRNA liposomes or cisplatin alone (p&lt;0.05). In conclusion, our preliminary studies indicate a potential advantage of using smart therapy by co-administering cisplatin with CCND1 siRNA-loaded liposomes.
Citation Format: Tanvi N. Gandhi, Chioniso P. Masamha, Sudip K. Das, Nandita G. Das. Smart therapy: Using CCND1-targeted siRNA-loaded liposomes to sensitize mantle cell lymphoma cells to cisplatin [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 3711.