bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 619: Identification of clinically actionable genomic alterations in the tumor and circulation of pancreatic cancer patients
Authors: Sausen Mark , Phallen Jillian , Adleff Vilmos , Jones Siân , Leary Rebecca J. , Lytle Karli , Parpart-Li Sonya , Murphy Derek , Barrett Michael T. , Linehan David C. , Maitra Anirban , Hruban Ralph , Von Hoff Daniel D. , Johansen Julia S. , Diaz Luis A. , Drebin Jeffrey A. , Velculescu Victor E. 
Published: August 2015

Abstract
Pancreatic adenocarcinoma has the worst overall mortality of any solid tumor, with only 6% of patients surviving after 5 years. To evaluate the clinical implications of genomic alterations in this low cellularity tumor type, we deeply sequenced the genomes of 134 enriched pancreatic adenocarcinomas from patients who underwent potentially curative resections. Given the low neoplastic cellularity of pancreatic cancers, we enriched for neoplastic cells either by macrodissection of primary tumors or by flow-sorting of tumor nuclei, and performed deep sequencing (high coverage) of these enriched samples using next-generation sequencing approaches. We obtained a total of &gt;1Tb of sequence data, resulting in an average coverage within the target regions of &gt;200-fold for each tumor analyzed by whole-exome sequencing and &gt;750-fold for each tumor analyzed by targeted cancer gene sequencing. These approaches allowed us to identify sequence changes, including single base and small insertion or deletion mutations, as well as copy number alterations in &gt;20,000 genes in the whole-exome analyses and in 116 specific genes in the targeted analyses. These analyses revealed that somatic mutation of chromatin remodeling genes were associated with improved progression-free and overall survival. Alterations in genes with potential clinical utility were observed in a majority of cases and included alterations of AKT1, AKT2, BRCA2, ERBB2, KIT, and PIK3CA. Non-invasive liquid biopsy analyses were performed before and after surgery to evaluate the presence of circulating tumor DNA in the plasma of 83 patients. Through these approaches, we were able to diagnose early stage pancreatic tumors in the majority of patients and to detect the presence of circulating tumor DNA prior to clinical relapse. These observations provide genetic markers of clinical outcome in pancreatic cancer and suggest new avenues for personalized therapy.
Citation Format: Mark Sausen, Jillian Phallen, Vilmos Adleff, Siân Jones, Rebecca J. Leary, Karli Lytle, Sonya Parpart-Li, Derek Murphy, Michael T. Barrett, David C. Linehan, Anirban Maitra, Ralph Hruban, Daniel D. Von Hoff, Julia S. Johansen, Luis A. Diaz, Jeffrey A. Drebin, Victor E. Velculescu. Identification of clinically actionable genomic alterations in the tumor and circulation of pancreatic cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 619. doi:10.1158/1538-7445.AM2015-619
Abstract 623: Evaluation of a multiplex biomarker assay for the detection of prostate cancer cells in urine
Authors: Nickens Kristen , Ali Amina , Scoggin Tatiana , Tan Shyh-han , Ravindranath Lakshmi , McLeod David , Tacha David , Sesterhenn Isabell , Dobi Albert , Srivastava Shiv , Petrovics Gyorgy 
Published: August 2015

Abstract
Background and Objectives: Over one million men undergo prostate biopsies annually in the US, a majority of them due to elevated serum PSA. More than half of the biopsies turn out to be negative for prostate cancer (CaP). The limitations of PSA test as well as the biopsy procedure have prompted to develop more precise CaP detection assays in urine- (e.g. PCA3, TMPRSS2-ERG) or blood (e.g. PHI, 4K). Here we describe the development and evaluation of a Urine CaP Marker Panel (UCMP) assay for sensitive and reproducible detection of CaP cells in post-digital rectal examination (post-DRE) urine.
Methods: The cellular content of the post-DRE urine, was captured on translucent membrane for direct evaluation by microscopy and immunocytochemistry. The membranes placed on Cytoclear microscope slides were used for characterization of prostate epithelial cell by PSA and Prostein or tumor cells by ERG and AMACR protein markers. Immunostained cells were analyzed for quantitative and qualitative features and correlated with biopsy positive and negative status for malignancy.
Results: Assay was optimized for single cell capture sensitivity and downstream evaluations by spiking known number of cells from established prostate cancer cell lines, LNCaP and VCaP, into cleared control urine. The cells captured from the post-DRE urine of subjects, obtained prior to biopsy procedure, were co-stained for ERG, AMACR, Prostein and PSA, rendering a whole cell based analysis and characterization. A feasibility cohort of 63 post-DRE urine specimens was assessed. Comparison of the UCMP results with the blinded biopsy results showed an assay sensitivity of 64% (16 of 25) and a specificity of 68.8% (22 of 32) for CaP detection by biopsy.
Conclusion: This pilot study assessing a minimally invasive prostate cancer detection assay with single cell sensitivity cell-capture and characterization from the post-DRE urine holds promise for further development of this novel assay platform.
Citation Format: Kristen Nickens, Amina Ali, Tatiana Scoggin, Shyh-han Tan, Lakshmi Ravindranath, David McLeod, David Tacha, Isabell Sesterhenn, Albert Dobi, Shiv Srivastava, Gyorgy Petrovics. Evaluation of a multiplex biomarker assay for the detection of prostate cancer cells in urine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 623. doi:10.1158/1538-7445.AM2015-623
Abstract 63: Alview (ALignment VIEWer): A software tool to visualize next generation sequencing (NGS) data
Authors: Meerzaman Daoud , Finney Richard , Chen Qing-Rong , Nguyen Cu , Hsu Chih Hao , Dunn Barbra 
Published: August 2015

Abstract
Widespread use of NGS has led to the increasing sizes of high throughput sequencing data of various types from different platforms. Review of alignment data by experienced genomics researchers is an important quality control element in this process. Key to this activity is visual inspection of the sequencing data in order to eliminate false positives and document the likelihood of true positives. Furthermore, such manual, or visual, examination of data must occur at extremely rapid speeds.
Alview (for “ALignment VIEWer”) is a compiled to native architecture software tool for visualizing the alignment of sequencing data. The inputs data are in the SAM/BAM format short read sequences that are aligned to a reference genome sequence. Outputs are images’ representing these short reads aligned to the reference genome. Alview is written in portable C with optional Graphical User Interface (GUI) code written in C,C++ or Objective C. Alview can be compiled to run in three different ways: (1) as a webserver, (2) as a command line tool, or (3) Alview is executable as a native graphical user interface. Alview is compatible with Microsoft Windows, Linux, and Apple OS X. Our new tool saves time and addresses specific regions of interest (for example, regions containing known or novel mutations or SNPS) and peruses these regions in the manner of a “slideshow”, enabling the scanning of a large number of samples in a short time
Citation Format: Daoud Meerzaman, Richard Finney, Qing-Rong Chen, Cu Nguyen, Chih Hao Hsu, Barbra Dunn. Alview (ALignment VIEWer): A software tool to visualize next generation sequencing (NGS) data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 63. doi:10.1158/1538-7445.AM2015-63
Abstract 636: Next-generation site-specific antibody-drug conjugates using the SMARTagTM technology platform
Authors: Kudirka Romas 
Published: August 2015

Abstract
The two clinically-approved antibody-drug conjugates, AdcetrisTM and KadcylaTM, demonstrate that targeting cytotoxic payloads directly to tumors is an effective clinical approach. However, at the molecular level, these therapeutics are composed of heterogeneous mixtures resulting from the nonselective ligation of cytotoxic payload to cysteine and lysine residues, respectively. The nonselective ligation approaches used to generate these two ADCs render it difficult to optimize their biological, physical, and pharmacological properties. Redwood Bioscience creates site-selective, stable linkages that allow us to design ADCs with enhanced efficacy, safety, and pharmacokinetics. Additionally, we are able to control payload stoichiometry and placement. Redwood Bioscience creates homogeneous ADCs using the SMARTagTM technology, in which a genetically encoded 5 amino acid “aldehyde-tag” sequence contains a cysteine that is cotranslationally converted to formylglycine via an enzymatic transformation. This method affords control over the placement of the reactive formylglycine aldehyde side chain, which can then be ligated using carbonyl bioconjugation methods. Here, we will present our novel protein modification platform—including our new conjugation chemistries and linker libraries—and its application to ADC generation. We will address SMARTagTM ADC safety, pharmacokinetics, and efficacy in preclinical tumor models, and discuss how these parameters are impacted by linker selection and payload placement on the antibody.
Citation Format: Romas Kudirka. Next-generation site-specific antibody-drug conjugates using the SMARTagTM technology platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 636. doi:10.1158/1538-7445.AM2015-636
Abstract 64: Targeting immune checkpoints: using a big data approach for their identification, prioritization and application
Authors: Kaw Sheetal , Upmanyu Sanatan , Sharma Himani , Nandabalan Krishnan 
Published: August 2015

Abstract
Tumor cells have long been known to successfully evade immune surveillance mechanisms.In order to curtail the tumor progression as well as to develop effective therapeutic anti-tumor strategies, key immune regulators,or so-called immune checkpoints, havebeen recognizedas playing an important role. To prevent excess tissue damage,immune checkpoints that refer to a number of inhibitory players involved in immune responses,are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses.Therapies targeting such immune checkpoints such as CTLA-4 and PD-1 have shown great clinical successas they boost the already existing immune response working against the tumorprogression. To identify novel immune checkpoints it becomes crucial to comprehensively analyze the wealth of existing knowledge regarding key signaling pathways, theircross-talk with immune regulators, protein expression profiles in tumor tissues, and patient outcomes data. These data silos require a big data analytics approach to successfully hypothesize, query and derive meaningful conclusions from this data. With a proprietary big data analytics platform PharmGPS™, we have identified a number of immune checkpoints that have clear therapeutic potential for solid tumor regenesis. First, second and third degree associations between tumorigenic pathways and immune checkpoints were identified and preliminary findings will be presented.
Citation Format: Sheetal Kaw, Sanatan Upmanyu, Himani Sharma, Krishnan Nandabalan. Targeting immune checkpoints: using a big data approach for their identification, prioritization and application. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 64. doi:10.1158/1538-7445.AM2015-64
Abstract 640: Probing the tumorigenic properties of two pore potassium channels using inhibitory anti-KCNK9 mAbs
Authors: Sun Han , Luo Liqun , Lal Bachchu , Laterra John , Li Min 
Published: August 2015

Abstract
Ion channels are important portals that facilitate ionic passage across membranes in all organisms. KCNK9, a member of the family of two-pore domain potassium K+ channels, mediates “leak” currents critical to maintaining cell resting membrane potentials. Since its identification, KCNK9 has been implicated in various human disorders including cancer. KCNK9 overexpression has been observed in melanoma, colorectal, breast and lung tumors and KCNK9 has been found to promote tumor survival and growth, by increasing resistance to hypoxia and apoptosis. However, KCNK9's underlying pathophysiologic mechanisms have been elusive due to the absence of specific inhibitors. Here, we describe the development of novel monoclonal antibodies directed against the KCNK9 extracellular domain and their molecular/cellular effects on KCNK9-expressing cells.
Murine monoclonal IgG1 antibodies were raised against recombinant KCNK9 extracellular domains expressed in a mammalian system. 40 monoclonal antibodies were generated and demonstrated channel subtype-specific recognition of human KCNK9. Among them, 1 antibody designated Y4-mAb displayed sub-nanomolar binding affinity and inhibited KCNK9 channel conductance by up to 30% when tested in a fluorescent ion-influx assay. Through confocal microscopic analysis, channel inhibition was found to result from antibody-induced internalization and endocytosis of cell-surface channels. Y4-mAb induced up to 30∼40% reduction in cell viability and increased cell death in BEN non-small cell lung carcinoma cells and BT-549 and 410.4 breast cancer cells. In addition to “direct cell killing”, this antibody activated complement, resulting in complement-dependent cancer cell cytotoxicity in vitro. Initial experiments in vivo showed that systemic Y4-mAb inhibited the capacity of BEN non-small cell lung carcinoma cells to propagate subcutaneous tumor xenografts in nude mice (p&lt;0.05).
In conclusion, we have generated a high affinity KCNK9-specific monoclonal antibody that perturbs KCNK9 function and inhibits tumor cell survival and xenograft formation. Anti-KCNK9 antibodies have the potential to be valuable research tools and may lead to novel therapeutics. Moreover, our strategies should be generally applicable to studying the functions of other ion channels in cancer.
Citation Format: Han Sun, Liqun Luo, Bachchu Lal, John Laterra, Min Li. Probing the tumorigenic properties of two pore potassium channels using inhibitory anti-KCNK9 mAbs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 640. doi:10.1158/1538-7445.AM2015-640
Abstract 649: Supramolecular assembly of antibody-drug conjugates using CORDLink platform for targeted drug delivery
Authors: Gupta Nimish , Kancharla Johny , Kaushik Shelly , Hossain Samad , Sarkar Arindam , Sengupta Aniruddha , Roy Monideepa , Sengupta Shiladitya 
Published: August 2015

Abstract
Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targeted drug delivery. However, the synthesis of novel linkers for generating stable ADCs remains a key goal in the development of effective ADCs. Here we describe a unique linker (CORDLink) platform technology based on coordination chemistry that maintains the integrity of the antibody without impacting binding to the target. Using an anti-HER2 monoclonal antibody and camptothecin, as examples of the targeting antibody and a highly cytotoxic payload respectively, we demonstrate that the linker enables the formation of a stable ADC via supramolecular coordinate bond. The robustness of our process and consistency was characterized through a variety of analytical tools, such as SE-HPLC, CEX-HPLC and HI-HPLC, while peptide mapping was done to elucidate the exact site of attachment. The ADCs were found to remain intact in media and serum using a fluorescence-based RP-HPLC method. The anti-HER2 antibody recognizes HER2 receptors on cancer cells inducing internalization of the conjugate. The ADC showed significant cytotoxicity in cells expressing HER2 receptor but not in HER2 negative cell lines with IC50s in the nM range. We have established robust characterization methods to validate and confirm the integrity of the prototype ADCs in vitro. Studies are underway to further evaluate these molecules in vivo. The CORDLink technology offers a highly versatile platform that can be leveraged to deliver a broad range of payloads to selected cells using different targeting molecules.
Citation Format: Nimish Gupta, Johny Kancharla, Shelly Kaushik, Samad Hossain, Arindam Sarkar, Aniruddha Sengupta, Monideepa Roy, Shiladitya Sengupta. Supramolecular assembly of antibody-drug conjugates using CORDLink platform for targeted drug delivery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2015-649
Abstract 65: An integrated bioinformatics approach for identifying patient-specific gene networks and novel therapeutic targets in glioblastoma
Authors: Stathias Vasileios , Pastori Chiara , Komotar Ricardo , Zhang Ming , Schürer Stephan , Clarke Jennifer , Ayad Nagi G. 
Published: August 2015

Abstract
The purpose of our approach is to identify highly relevant and patient specific gene networks from next generation sequencing data and use the resulting gene combinations to identify potential novel therapeutic targets.
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Despite medical advances in the field, the median survival time is still below 2 years since recurrence is nearly universal. Thus, the discovery of novel and specific molecular targets is needed.
As with all cancers, GBM arises due to complex alterations in a patient's genome. Identifying patient-specific differentially expressed genes (DEGs) though, can impose many difficulties given the discordance of different analysis methods when the sample size is low. We used the data on the large number of GBM patients within TCGA (The Cancer Genome Atlas) as filter for identifying variations in expression. With the help of our algorithm, we produced enriched single patient RNAseq DEG lists and we calculated a hypergeometric probability and a correlation coefficient for every gene pair on these lists. By using the most significant of these pairs, we generated gene association networks. To further validate the biological relevance of the gene pairs, we looked into the presence of these networks in other types of cancer and searched for published experimental data supporting the connections of our networks. In order to assess the therapeutic potential of these genes, we used complimentary experiments involving GBM cell lines recorded through the LINCS (Library of Integrated Network-based Cell Signatures) database.
This study identifies a putative workflow for uncovering differentially expressed patient specific genes and gene networks for GBM, and capitalizes on the LINCS database to assess the potential of novel therapeutic targets.
Citation Format: Vasileios Stathias, Chiara Pastori, Ricardo Komotar, Ming Zhang, Stephan Schürer, Jennifer Clarke, Nagi G. Ayad. An integrated bioinformatics approach for identifying patient-specific gene networks and novel therapeutic targets in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 65. doi:10.1158/1538-7445.AM2015-65
Abstract 650: A high-throughput conjugation strategy for the selection of THIOMAB™ antibodies with desired properties for antibody-drug conjugation
Authors: Ohri Rachana V. , Bhakta Sunil , Raab Helga , Vandlen Richard , Junutula Jagath , Erickson Hans 
Published: August 2015

Abstract
THIOMAB™ antibody technology utilizes antibody engineering to replace endogenous amino acids of an antibody with cysteine to allow for site-selective conjugation. The technology enables the exploration of different drug attachment sites on the antibody thereby offering the potential to select antibody-drug conjugates (ADCs) with unique properties. Having a large number of antibody sites from which to choose may be desired for some applications. Many antibody sites are not suitable due to limited solvent accessibility or because drug attachment alters the native antibody properties. To identify those antibody sites most amenable to drug conjugation, we prepared 648 THIOMAB™ antibody variants of the anti-HER 2 antibody 4D5 by sequentially mutating every amino acid in the light and heavy chains to cysteine (excluding the endogenous cysteines). Each THIOMAB™ antibody variant was then conjugated to maleimido caproyl valine citrulline PABA MMAE and pyridyl disulfide MMAE in separate reactions. A high throughput on-bead Protein A conjugation and purification method was developed using a 96 well plate format. Complete reduction of the engineered cysteines and reoxidation of the endogenous cysteines, and drug to antibody ratios (DAR) were all determined by LC/MS. The concentration and aggregation status of each ADC were determined using automated liquid chromatography methods. Nearly 40% of the THIOMAB™ antibodies were found to be suitable for conjugation with DAR &gt;1 and low aggregation levels. The other 60% failed due to a variety of factors including low drug incorporation, high aggregation levels, and incomplete re-oxidation of the endogenous cysteines. We found similar results with the maleimide and pyridyl disulfide derivatives suggesting our findings may be applicable to other auristatin derivatives with different sulfhydryl reactive chemistries. In summary, we have developed a high throughput conjugation strategy for THIOMAB™ antibodies and used it to identify the antibody sites most suitable for conjugation to auristatin derivatives.
Citation Format: Rachana V. Ohri, Sunil Bhakta, Helga Raab, Richard Vandlen, Jagath Junutula, Hans Erickson. A high-throughput conjugation strategy for the selection of THIOMAB™ antibodies with desired properties for antibody-drug conjugation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 650. doi:10.1158/1538-7445.AM2015-650