bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-134: Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic cancer
Authors: Capello Michela , Bantis Leonidas E. , Scelo Ghislaine , Zhao Yang , Dhillon Dilsher S. , Wang Hong , Abbruzzese James L. , Maitra Anirban , Tempero Margaret A. , Brand Randall , Firpo Matthew A. , Mulvihill Sean , Katz Matthew H. , Brennan Paul , Feng Ziding , Hanash Samir M. , Taguchi Ayumu 
Published: July 2016

Abstract
Purpose: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19.9. We have carried out sequential validations starting with 32 protein biomarker candidates to develop a marker panel to improve detection of early stage disease compared with CA19.9 alone.
Patients and Methods: Multiple independent sample sets consisting of PDAC cases, benign pancreatic disease and healthy controls were utilized for immunoassays of candidate markers which after sequential validations yielded a panel of three markers that was further tested in a blinded setting.
Results: The 32 biomarker candidates were initially tested in a sample set consisting of 75 PDAC cases, 29 healthy controls, and 19 chronic pancreatitis cases which narrowed the list to seven biomarker candidates. A second independent set of 73 early-stage PDAC cases, 60 healthy controls, and 74 benign pancreatic disease cases (60 chronic pancreatitis cases and 14 benign pancreatic cyst cases) yielded a panel of three markers, including CA19-9, with an AUC (95%CI) of 0.949 (0.917-0.981) and sensitivity of 0.849 at 95% specificity. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy controls, yielding an AUC of 0.887. The performance of the biomarker panel was significantly improved compared to CA19-9 alone (P &lt; 0.001) in both plasma sample sets.
Conclusion: We validated a protein-based three marker panel with significantly improved performance compared to CA19-9 with the potential to contribute to strategies for detecting early-stage PDAC.
Citation Format: Michela Capello, Leonidas E. Bantis, Ghislaine Scelo, Yang Zhao, Dilsher S. Dhillon, Hong Wang, James L. Abbruzzese, Anirban Maitra, Margaret A. Tempero, Randall Brand, Matthew A. Firpo, Sean Mulvihill, Matthew H. Katz, Paul Brennan, Ziding Feng, Samir M. Hanash, Ayumu Taguchi. Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-134.
Abstract LB-156: Delineating the pathological roles and molecular functions of histone methyltransferase G9a in hepatocellular carcinoma
Authors: Wei Lei , Tsang Felice Ho-Ching , Au Sandy Leung-Kuen , Lee Joyce , Wong Carmen , Ng Irene Oi-Lin , Wong Chun-Ming 
Published: July 2016

Abstract
Liver cancer, primarily hepatocellular carcinoma (HCC), is the third leading cause of cancer mortality worldwide. In HCC, epigenetic changes including aberrant DNA methylations and histone modifications occur far more frequently than genetic alternations. However, the underlying mechanism and specific gene targets are still unknown. Using RNA-Sequencing, we identified Euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a) as one the most significantly deregulated epigenetic regulatory genes in human HCC. G9a is a SET domain containing histone methyltransferase specific for histone H3 lysine 9 methylation. However, little is known about the functional roles of G9a in human HCC. Herein, we showed that G9a expression was frequently up-regulated in primary HCC. Up-regulation of G9a was significantly associated with multiple clinicopathological features related to HCC metastasis. We demonstrated that the frequent G9a up-regulation in HCC was attributed to the G9a gene copy number gain. In addition, we identified miR-1 as a novel post-transcriptional regulator of G9a. Loss of miR-1 significantly contributed to G9a up-regulation in human HCC. Functionally, stable knockdown (by lenti-viral based shRNA) and genetic knock-out of G9a (by CRISPR/Cas9 gene editing system) significantly suppressed HCC cell proliferation, migration and colony formation. We also demonstrated that G9a specific inhibitors, UNC0638 and BIX01294, could effectively inhibit HCC cell growth. By utilizing nude mice model, we showed that depletion of G9a drastically inhibited in vivo tumorigenicity of HCC cells. Mechanistically, we found that up-regulation of G9a epigenetically silence the expression of tumor suppressive gene RARRES3 to promote HCC tumorigenicity and metastasis. In summary, our finding suggested that up-regulation of G9a contributed to the liver carcinogenesis and could be a therapeutic target for HCC treatment.
Citation Format: Lei Wei, Felice Ho-Ching Tsang, Sandy Leung-Kuen Au, Joyce Lee, Carmen Wong, Irene Oi-Lin Ng, Chun-Ming Wong. Delineating the pathological roles and molecular functions of histone methyltransferase G9a in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-156.
Abstract LB-164: DNA ligase IV modulates the cellular response to DNA replication stress
Authors: Hooks Grace , Anchondo Yasmin , Sharma Neelam , Nickoloff Jac , Ashley Amanda 
Published: July 2016

Abstract
Correctly repairing DNA damage is crucial to the survival and genomic integrity of cells. Double strand breaks (DSBs) are particularly problematic DNA damage; failure to properly repair DSBs can precede genomic instability leading to cancer. Because of the high proliferative index of cancer cells, replication toxins are successfully used to treat cancer. The two major DNA DSB repair pathways are homologous recombination and nonhomologous end-joining (NHEJ). DNA ligase IV is a central component of NHEJ, performing the final ligation step to reseal the broken DNA ends, in concert with XRCC4. We determined cells lacking the early acting NHEJ protein, and DNA damage response signaling kinase, DNA-PK, restarted DNA replication forks quicker than wild-type following replication stress. The role of other NHEJ proteins in replication fork restart is unclear. Our goal was to investigate whether ligase IV, a protein that appears to function exclusively in NHEJ, is involved in the replication stress response. We tested the hypothesis that ligase IV delays replication restart following exposure to replication toxins. Ligase IV knockdown was confirmed by qPCR and western blotting. siRNA knockdown of ligase IV alone reduced cell viability and it reduced EdU incorporation after replication stress. The opposite effects of DNA-PK and ligase IV on the speed of replication fork restart suggests that NHEJ, per se, does not directly affect replication fork restart. We previously demonstrated that DNA-PK regulates replication fork restart, at least in part, by phosphorylating RPA32, which in turn regulates ATR activation and downstream checkpoint functions. Ligase IV deficiency may influence replication fork restart indirectly, for example, by causing spontaneous DSBs to persist longer, limiting availability of repair factors needed for fork restart (saturation effect). A not mutually exclusive possibility is that fork restart is hindered by persistent DSBs due to checkpoint activation. Understanding how NHEJ proteins impact the replication stress response may provide opportunities for developing more effective cancer treatments.
Citation Format: Grace Hooks, Yasmin Anchondo, Neelam Sharma, Jac Nickoloff, Amanda Ashley. DNA ligase IV modulates the cellular response to DNA replication stress. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-164.
Abstract LB-175: ATM regulates radiation-induced translational control of gene expression
Authors: Lehman Stacey L. , Wahba Amy , Camphausen Kevin , Tofilon Philip J. 
Published: July 2016

Abstract
The cellular radioresponse is composed of processes regulated by constitutively expressed proteins and processes regulated by new gene expression. While processes regulated by constitutively expressed proteins, such as those participating in DNA repair and cell cycle arrest, have been extensively studied, the radiation-induced changes in gene expression are not well defined. Previously, we have demonstrated that translation plays an important role in regulating gene expression in response to radiation. In glioblastoma cells, treatment with radiation affects more genes at the translational level than at the transcriptional level. Specific transcripts were found to be recruited to or away from polysomes without global changes in the polysome profile of the cells. Here, we utilized microarray analysis of polysome-associated transcripts in the glioblastoma stem-like cell line NSC11 to demonstrate that the DNA damage response kinase ATM controls the translation of a subset of genes as part of the radioresponse. Cells were incubated with the ATM inhibitor KU-60019 at a dose of 500nM for one hour, exposed to 2 Gy, and harvested for polysome extraction one hour after irradiation. ATM inhibition blocked translational changes of approximately one third of genes that were affected by radiation. Gene enrichment analysis revealed that genes translationally regulated by ATM were significantly involved in a number of cellular processes, indicating that ATM-mediated translational control may have functional consequences on the cellular radioresponse. By GSEA, cells treated with radiation alone were highly enriched for terms involving mitochondrial structure and function, cellular respiration, and oxidative stress as compared to irradiated cells treated with the ATM inhibitor. Other significantly enriched categories of functional interest included the spliceosome, RNA catabolic processes, the small nuclear ribonucleoprotein complex, and phospholipid and phosphoinositide metabolism. Analysis of UTR regulatory elements revealed that a significant percentage of the genes translationally upregulated by ATM in irradiated cells were enriched for HuR binding sites, which suggests a potential mechanism for polysome recruitment of these transcripts. Overall, these findings uncover a novel network of post-transcriptional gene regulation orchestrated by ATM and provide a framework to identify potential new molecules and pathways that govern tumor cell radiosensitivity.
Citation Format: Stacey L. Lehman, Amy Wahba, Kevin Camphausen, Philip J. Tofilon. ATM regulates radiation-induced translational control of gene expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-175.
Abstract LB-194: AhR Arg554Lys impacts tumor ER expression and endocrine treatment response in breast cancer
Authors: Simonsson Maria , Markkula Andrea , Rose Carsten , Ingvar Christian , Jernström Helena C. 
Published: July 2016

Abstract
Introduction: Markers for treatment resistance in breast cancer are needed. The Aryl hydrocarbon receptor (AhR) is involved in the regulation of estrogen metabolism. Previous studies have observed a crosstalk between AhR and the estrogen receptor (ER), indicating that the AhR may be of importance in the response of endocrine treatment.
Materials and methods: A functional polymorphism in the AhR Arg554Lys (G&gt;A) was analyzed in a cohort of 634 breast cancer patients included at their preoperative visits in Lund, Sweden between 2002 and 2008. AhR genotypes were studied in relation to ER status and risk for breast cancer events.
Results: The frequencies of the AhR GG/ GA/ AA genotypes were 82.0%, 16.7%, and 1.3%, respectively. There was a trend towards increasing frequency of ER+ tumors with increasing number of A-alleles (P-trend = 0.03). Since few patients had the A/A genotype, patients with the G/A and A/A genotypes were combined in the survival analyses of the 576 patients with invasive tumors, no preoperative treatment, and no events detected on the postoperative metastases screen.
Overall, AhR was not associated with event-free survival (LogRank P = 0.22). Among patients ever treated with chemotherapy or radiotherapy, AhR was not associated with event-free survival (LogRank P = 0.24 and P = 0.18, respectively). However, among tamoxifen-treated patients with ER+ tumors, AhR G/G carriers had a significantly lower risk for breast cancer events (LogRank P = 0.005), adjusted HR 0.53 (95% CI 0.29-0.94). This association was confined to patients who had received both tamoxifen and aromatase inhibitor (AI) switch treatment (LogRank P = 0.0002), adjusted HR 0.23 (0.09-055), while no association was seen in patients treated with tamoxifen only (LogRank P = 0.56).
AI-treated patients with the G/G genotype had an even lower risk for breast cancer events than tamoxifen-treated patients (LogRank P = 0.005), adjusted HR 0.39 (0.19-0.81). Again this was only seen in patients who had received both AI and tamoxifen, but not in patients who had received AI but no tamoxifen treatment. Adjustments were made for age at inclusion, axillary lymph node involvement, invasive tumor size, and histological grade. Further adjustment for smoking status did not materially change the results.
Conclusion: The functional AhR Arg554Lys polymorphism may impact tumor ER expression and response to endocrine switch treatment with both AI and tamoxifen in breast cancer patients.
Citation Format: Maria Simonsson, Andrea Markkula, Carsten Rose, Christian Ingvar, Helena C. Jernström. AhR Arg554Lys impacts tumor ER expression and endocrine treatment response in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-194.
Abstract LB-221: Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates (ADCs) demonstrate tumor specificity, unique sequence homology and in vitro and in vivo antitumor efficacy
Authors: Eaverone David , Behrens Jeff , Prendergast Jillian 
Published: July 2016

Abstract
Siamab Therapeutics is developing monoclonal antibodies and antibody drug conjugates (ADCs) targeting tumor-associated carbohydrate antigens such as Sialyl-Tn (STn). These antibodies are selected using a proprietary glycan microarray that enriches for candidates whose binding is protein independent, highly specific and demonstrates exceptional target affinity. STn is a cancer specific antigen that is expressed on the surface of carcinomas including ovarian, colon, prostate, and pancreatic tumors but is rarely present in normal tissue. STn expression has been linked to innate immune suppression, a chemoresistant phenotype, metastasis, and poor prognosis. Previous attempts to target this antigen in the clinic with synthetic glycan vaccines proved safe but lacked efficacy.
Siamab has developed over 20 murine mAbs that bind STn with high affinity and specificity. When formatted as ADCs, anti-STn mAb-ADCs target and selectively kill STn expressing cells and also demonstrate efficacy in multiple xenograft studies. Multiple murine mAbs perform well in IHC studies with multiple solid tumor samples and tissue microarrays and demonstrate high tumor specificity. Remarkable sequence homology across all murine mAbs was observed in both heavy and light chains, and hot spots for hypermutation were identified. Humanization was successfully completed using a selection of mAbs and multiple humanized mAbs maintain their target specific binding, affinity and cytotoxicity in vitro. Our data demonstrates that high-affinity, STn-specific mAbs show promise both as therapies for solid tumors and as a potential tool for the development of biomarkers and companion diagnostics enabling selection of patients most likely to respond to therapy.
Citation Format: David Eaverone, Jeff Behrens, Jillian Prendergast. Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates (ADCs) demonstrate tumor specificity, unique sequence homology and in vitro and in vivo antitumor efficacy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-221.
Abstract LB-225: Combination immunotherapy targeting HSP90 DNA-repair client proteins overexpressed in chemotherapy-resistant melanoma
Authors: Raveendran Subhara , Fecek Ronald , Carey Cara Donahue , Storkus Walter J. 
Published: July 2016

Abstract
DNA repair protein (DNA-RP) overexpression has been reported to involve post-translational protein stabilization mediated by the molecular chaperone heat shock protein 90(HSP90), thereby preventing proteasome-dependent degradation of these HSP90 “client” proteins. Overexpression of DNA-RP in a disease-stage associated manner has also been correlated to chemo resistance and poor overall prognosis. Hence, HSP90 inhibitors (HSP90i) have been heralded as co-therapy agents for cancer patients that have developed resistance to first-line treatments such as temozolomide (TMZ). In the presence of HSP90i, HSP90 client proteins rapidly become (poly)ubiquinated and undergo degradation resulting in the improved sensitization of cancer cells to chemo therapy. We observed that HSP90i promote the proteasome-dependent degradation of a broad range of DNA-repair client proteins. We have also identified 9 H-2Kb/Db-presented peptide epitopes derived from DNA-RPs that may be recognized by Type-1 CD8+ T cells after specific vaccination. When combined with adoptive cell therapy using DNA-RP-specific CD8+ T cells, HSP90i cotreatment yielded superior anti-tumor efficacy against established TMZ-resistant B16 tumors in C57BL/6 mice.
Citation Format: Subhara Raveendran, Ronald Fecek, Cara Donahue Carey, Walter J. Storkus. Combination immunotherapy targeting HSP90 DNA-repair client proteins overexpressed in chemotherapy-resistant melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-225.
Abstract LB-228: Polo-like kinase 4: A potential new target for the management of prostate cancer
Authors: Singh Chandra K. , Shabbir Maria , Nihal Minakshi , Iczkowski Kenneth A. , Ahmad Nihal 
Published: July 2016

Abstract
Prostate cancer (PCa) is the most prevalent non-cutaneous cancer of males. According to an estimate from the American Cancer Society, it is expected that approximately 180,890 new cases of PCa will be diagnosed and 26,120 PCa-related deaths will occur in the United States in 2016. Therefore, identification of additional molecular target(s) could be useful in designing novel mechanism-based approaches for the prevention and/or therapy of PCa. PLK4 belongs to the polo-like kinase family of serine/threonine protein kinases that localizes to centrioles and regulates centriole duplication during the cell cycle. Essentially, PLK4 is a low abundance suicidal kinase that is known to auto-phosphorylate itself to promote its own destruction to limit centriole duplication once per cell cycle phase. Since centrosome aberrations are frequently seen in cancer, the central role of PLK4 in centriole duplication suggests its significance as a potential target for cancer management. However, the role and functional relevance of PLK4 in PCa development and progression has not been investigated. In this study, we determined the expression profile of PLK4 in PCa using immunohistochemical analysis of multiple tissue microarrays (TMAs) containing a variety of cancerous and benign human prostate tissues. The TMAs were immunostained for PLK4 and the images were scanned and analyzed for protein levels using Aperio ScanScope at 40x magnification. We found a significant upregulation of PLK4 in PCa, compared to benign prostatic tissues. Further, we found a significant upregulation of PLK4 protein and mRNA in human PCa cells, as assessed by western blot and qRT-PCR analyses, respectively. To further assess the relevance of PLK4 overexpression in PCa, we determined the effect of a small molecule inhibitor of PLK4, centrinone-B, on androgen-responsive 22Rν1 and androgen-independent DU145 human PCa cells. Centrinone-B treatment (0, 50, 100 and 200 nM; for 24 and 48 h) resulted in a marked decrease in growth and viability of PCa cells, as assessed i) by CytoTox-Glo™ cytotoxicity assay, and ii) microscopic evaluation of cells following staining with Nuclear Fast Red and Crystal Violet dyes. Further, centrinone-B treatment resulted in a G1 phase cell cycle arrest of human PCa cells. Taken together, our study provides first direct evidence of a pro-proliferative function of PLK4 in PCa. However, additional studies are required to ascertain the relevance of our in vitro findings to in vivo situations in relevant animal models.
Citation Format: Chandra K. Singh, Maria Shabbir, Minakshi Nihal, Kenneth A. Iczkowski, Nihal Ahmad. Polo-like kinase 4: A potential new target for the management of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-228.