tbuckley/cabot-search huggingface dataset:
Abstract 3662: Design and development of a novel series of HDAC6-selective inhibitors for the treatment of hematological and solid tumors
Authors: Stephen J. Shuttleworth
Journal: Cancer Research (2015)

Abstract Inhibition of the zinc-dependent histone deacetylase (HDAC) family of enzymes has been pursued as a clinical strategy in cancer for many years. HDACs regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression; by removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. The current landscape of HDAC-targeting therapeutics has, however, been dominated by pan-inhibitors that regulate the activity of most, if not all, of the HDAC family members which, through dysregulation of expression of a myriad of genes, has led to agents with undesirable toxicities and narrow therapeutic margins. Recently, however, attention has begun to turn to the role of specific HDAC isoforms in tumorigenesis and, in turn, the development of more selective therapeutics. HDAC6 has emerged as a particularly interesting target as it plays an essential role in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. Further, recent evidence has emerged of HDAC modulating immune-related pathways in solid tumors, notably regulating PDL-1 expressions through STAT3 modulation. This presentation will outline the design and development of a new class of highly-potent, selective and orally-active HDAC6 inhibitors with the potential in the treatment of multiple tumor types. Uniquely, this series of compounds has been designed such that selectivity levels for HDAC6 over other isoforms can be finely regulated, enabling the investigation of preferred levels of HDAC6 specificity for therapy, and opening possibilities for broader combination modalities in a clinical setting. Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of HDAC6-selective inhibitors for the treatment of hematological and solid tumors. [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 3662. doi:10.1158/1538-7445.AM2015-3662
Identification of a novel urothelial carcinoma (UC) biomarker of lethality.
Authors: J. E. Rosenberg, L. Werner, S. Selvarajah, B. Weir, M. M. Regan, S. J. Jacobus, D. M. Berman, F. A. B. Schutz, R. O'Brien, T. K. Choueiri, J. Barretina, S. Signoretti, M. Loda, E. A. Guancial, E. Gallardo, F. G. Rojo, J. Lloreta, W. C. Hahn, P. W. Kantoff, J. Bellmunt
Journal: Journal of Clinical Oncology (2011)

4569 Background: Limited information exists regarding the changes that occur in UC tumors that ultimately metastasize, the lethal phenotype of UC. Recurrent copy number alterations (CNAs) have been previously identified in UC, but correlation with clinical outcomes has not been reported in metastatic UC. Methods: We identified a cohort of 94 UC patients uniformly-treated for distant metastases (platinum-based combination chemotherapy), with clinical annotatation and FFPE primary tumor tissue available. Overall survival (OS) was defined as the time from start of chemotherapy for metastatic disease to death or last follow-up. Tumor bearing areas were evaluated by a single pathologist, and genomic DNA was extracted and analyzed for copy number alterations using Agilent 4x180k high resolution comparative genomic hybridization (CGH) arrays (average resolution of 13kb). Gain and Loss Analysis of DNA (GLAD) was used to segment the array output, and Genomic Identification of Significant Targets in Cancer (GISTIC) v2 was used to assess the significance of gains/losses (log base 2 ratio > 0.9 and < -1.3, respectively). False discovery rates < 0.2 were considered significant to correct for multiple comparisons. A Cox model for survival controlling for known prognostic variables (PS and visceral metastasis) was used for analysis. Bootstrapping (500 re-samples) assessed the variability and bias of parameters as internal validation. Results: In the 94 patients (46 deaths) median OS was 15 months. 15 patients were noted to have copy number gain (CNG) of a 150 kb region of 1q23.3. These patients had a median OS of 7.3 months, compared to patients without CNG with a median OS of 18 months. Gain of 1q23.3 is significantly associated with lethal UC (adjusted HR 2.94, 95% CI 1.35-6.44, p=0.007, FDR=0.12) (Table). This finding was internally validated (HR=3.2, 95% CI 1.25-7.2). Conclusions: Genomic gain of a short segment of chromosome 1q23.3 is associated with a lethal phenotype of UC in patients with metastatic disease. External validation in an additional cohort is underway. HR (95% CI) P value 1q23.3 gain (yes vs. no) 2.94 (1.35, 6.44) 0.007 ECOG PS (1,2 vs. 0) 1.93 (1.00, 3.79) 0.05 Visceral disease (yes vs. no) 2.40 (1.25, 4.47) 0.008
Abstract 649: Supramolecular assembly of antibody-drug conjugates using CORDLink platform for targeted drug delivery
Authors: Nimish Gupta, Johny Kancharla, Shelly Kaushik, Samad Hossain, Arindam Sarkar, Aniruddha Sengupta, Monideepa Roy, Shiladitya Sengupta
Journal: Cancer Research (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 LB-220: Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma
Authors: A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, E. G. Flores, B. Kendrick, D. Lapid, A. Powers, S. Kanodia, S. Pastorino, H. I. Pass, V Dixit, H. Yang, M. Carbone
Journal: Cancer Research (2015)

Abstract Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma (MM). MM pathogenesis is generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure. In a set of short-term experiments, we intraperitoneally injected BAP1+/- and wild-type littermates with low doses of asbestos fibers and analyzed the inflammatory response both at a cellular and humoral level. In a long-term experiment following a similar protocol, we assessed the incidence of MM in mice with and without germline BAP1 mutations and their survival. We found that, compared to their wild type littermates, BAP1+/- mice exposed to low doses of asbestos fibers showed significant alterations of the peritoneal inflammatory response. In particular, we observed significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1+/- mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, and shorter survival. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response. Citation Format: A. Napolitano, L. Pellegrini, A. Dey, D. Larson, M. Tanji, E. G. Flores, B. Kendrick, D. Lapid, A. Powers, S. Kanodia, S. Pastorino, H. I. Pass, V Dixit, H. Yang, M. Carbone. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. [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 LB-220. doi:10.1158/1538-7445.AM2015-LB-220
Reliability of specific physical examination tests for the diagnosis of shoulder pathologies: a systematic review and meta-analysis
Authors: Toni Lange, Omer Matthijs, Nitin B Jain, Jochen Schmitt, Jörg Lützner, Christian Kopkow
Journal: British Journal of Sports Medicine (2016)

Background Shoulder pain in the general population is common and to identify the aetiology of shoulder pain, history, motion and muscle testing, and physical examination tests are usually performed. Objective The aim of this systematic review was to summarise and evaluate intrarater and inter-rater reliability of physical examination tests in the diagnosis of shoulder pathologies. Methods A comprehensive systematic literature search was conducted using MEDLINE, EMBASE, Allied and Complementary Medicine Database (AMED) and Physiotherapy Evidence Database (PEDro) through 20 March 2015. Methodological quality was assessed using the Quality Appraisal of Reliability Studies (QAREL) tool by 2 independent reviewers. Results The search strategy revealed 3259 articles, of which 18 finally met the inclusion criteria. These studies evaluated the reliability of 62 test and test variations used for the specific physical examination tests for the diagnosis of shoulder pathologies. Methodological quality ranged from 2 to 7 positive criteria of the 11 items of the QAREL tool. Conclusions This review identified a lack of high-quality studies evaluating inter-rater as well as intrarater reliability of specific physical examination tests for the diagnosis of shoulder pathologies. In addition, reliability measures differed between included studies hindering proper cross-study comparisons. Trial registration number PROSPERO CRD42014009018.
Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins
Authors: Yuee Cai, Jinming Zhang, Nelson G. Chen, Zhi Shi, Jiange Qiu, Chengwei He, Meiwan Chen
Journal: Medicinal Research Reviews (2016)

Abstract Tannins, polyphenols in medicinal plants, have been divided into two groups of hydrolysable and condensed tannins, including gallotannins, ellagitannins, and (–)‐epigallocatechin‐3‐gallate (EGCG). Potent anticancer activities have been observed in tannins (especially EGCG) with multiple mechanisms, such as apoptosis, cell cycle arrest, and inhibition of invasion and metastases. Furthermore, the combinational effects of tannins and anticancer drugs have been demonstrated in this review, including chemoprotective, chemosensitive, and antagonizing effects accompanying with anticancer effect. However, the applications of tannins have been hindered due to their poor liposolubility, low bioavailability, off‐taste, and shorter half‐life time in human body, such as EGCG, gallic acid, and ellagic acid. To tackle these obstacles, novel drug delivery systems have been employed to deliver tannins with the aim of improving their applications, such as gelatin nanoparticles, micelles, nanogold, liposomes, and so on. In this review, the chemical characteristics, anticancer properties, and drug delivery systems of tannins were discussed with an attempt to provide a systemic reference to promote the development of tannins as anticancer agents.
Abstract 940: Identification of Palbociclib response signature across indications
Authors: Xianxian Zheng, Mark Ozeck, Zhou Zhu, Keith Ching, David Shields, James Hardwick, Paul Rejto, Todd VanArsdale
Journal: Cancer Research (2015)

Abstract Cellular proliferation is dependent on an orderly movement through the various phases of cell cycle. Progression through the G1 phase in particular requires phosphorylation of the retinoblastoma (Rb) protein which in turn releases E2F transcription factors resulting in transcriptional activation of response gene necessary for progression into S-phase. The cyclin D-CDK4/6 signaling pathway represent a critical regulatory pathway controlling transition from G1 into S-phase and greater than 90% of human tumors have mutations in this pathway. Palbociclib is a potent, selective, and orally bioavailable inhibitor of Cdk4/6. In human tumor xenograft models, Palbociclib has significant antitumor activities. The clinical activities of Palbociclib have also be demonstrated in the phase II PALOMA-1 trial for dramatic efficacy of postmenopausal patients with locally advanced or newly diagnosed estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer in combination with letrozole. To better understand the molecular mechanisms of Palbociclib response, we have identified a common set of gene signatures for ER+ BC as well as melanoma models. The physiological role of these genes regulated by Palbociclib is associated with DNA replication and repair, cell cycle, signal transduction, and Mitosis. Many of these genes have been previously identified as E2F signatures. In this study, we are aiming to expand this analysis to include two additional indications including Head and Neck squamous cell carcinoma (HNSCC) as well as squamous cell lung carcinoma (Sq lung) using Illumina RNASeq technology platform. Results from these studies will be presented and core Palbo-response signature will be discussed. In addition, we will also present the pharmacological effects of Letrozole on the gene expression changes for these core signatures in ER+ BC models. Citation Format: Xianxian Zheng, Mark Ozeck, Zhou Zhu, Keith Ching, David Shields, James Hardwick, Paul Rejto, Todd VanArsdale. Identification of Palbociclib response signature across indications. [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 940. doi:10.1158/1538-7445.AM2015-940
191. Frataxin: A Putative Biomarker for Minimal Effective Dosage of AAV Gene Therapy
Authors: Thiago Love-Leonor, Manuela Corti, Sanford Boye, Amy Donate, Katherine Santostefano, Denise Cloutier, Nathalie Clemente, Christina Pacak, Barry Byrne
Journal: Molecular Therapy (2015)

Friedrich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a triplet repeat expansion in the frataxin gene (FXN), which encodes the mitochondrial protein frataxin. Deficiency in frataxin expression results in severe mitochondrial dysfunction leading to progressive gait abnormality, impaired muscle coordination, muscle weakness, hyporeflexia, dysmetria, dysarthria, and hypertrophic cardiomyopathy. Currently, there are no approved treatments for FRDA, which is the most common occurring autosomal recessive ataxia, affecting 1 in 50,000 people worldwide. Precise quantification of frataxin levels is critical for establishing the effectiveness of potential therapies. Therefore, methods that improve detection of FXN expression will facilitate the implementation of novel therapies into a clinical setting. Our overall objective is to establish an approach for effective gene transfer and quantification of frataxin levels sufficient to restore mitochondrial function. Stable isotope labeling of amino acids in cell culture or in mammals (SILAC/M) is a novel and sensitive mass spectrometry based approach we propose for the quantification of frataxin levels; therefore enabling determination of required levels for correction of FXN deficiency. We have generated a rAAV2/9-FXN vector expressing codon optimized human FXN for use in models of FRDA. Renal epithelial cells (REC) were isolated from control and FRDA patients, and was SILAC used to quantify AAV-mediated FXN expression in-vitro. Induced pluripotent stem cells (IPSC) were generated from REC's, and subsequently differentiated to cardiomyocytes and neurons. AAV-mediated correction of FXN was verified by increased mitochondrial activity including reduced iron deposition and increased aconitase function in FRDA cells. Preliminary results show that SILAC/M are able to accurately measure endogenous and vector derived FXN expression in-vitro and in-vivo. Moreover, improvement in mitochondrial function was correlated with levels of FXN expression in vitro. Future studies will involve systemic dosing of rAAV9-FXN in a novel model of FRDA.
Abstract 4856: ITD Assembler: An algorithm for internal tandem duplication discovery from short-read sequencing data
Authors: Oliver A. Hampton, Navin Rustagi, Jie Li, Liu Xi, Richard A. Gibbs, Sharon E. Plon, Marek Kimmel, David A. Wheeler
Journal: Cancer Research (2015)

Abstract Tandem duplication of coding sequence is an important mechanism of somatic mutation capable of activating oncogenes such as fms-related tyrosine kinase 3 (FLT3) as well as the potential for underlying constitutional or germline disease. Detection of internal tandem duplication (ITD) in short-read sequencing data remains challenging due to deficiencies in short-read alignment where reads carrying signatures of ITD are often unmapped. Assembly based approaches collapse repetitive sequences, resulting in reduced or lost genomic complexity. The majority of structural variation detection tools are limited to finding insertions that are contained entirely within individual read alignments, and are unable to detect read-spanning duplications. Tools designed to detect large structural variation from paired-end reads that map discordantly based on expected fragment size and orientation do not provide the precision needed to detect ITDs. Only tools that consider the characteristic alignment features that signal the presence of ITDs will be able to detect them; these alignment features include: an excess of reads with unaligned, soft-clipped bases, read pairs where one end is unmapped located near the site of insertion, and read pairs where both ends are unmapped. We introduce ITD Assembler, a novel approach that searches all unmapped reads from exome capture or whole genome sequencing data to identify duplications. From the entire set of unmapped reads plus subset of mapped reads harboring soft-clipped bases, de Bruijn graph assembly is applied to select reads that form cycles, indicative of duplicated sequence structures. Reads from de Bruijn graph cycles are then assembled using an Overlap Layout Consensus (OLC) methodology thereby alleviating the collapse of repeat sequences affecting de Bruijn graph assembly approaches. Resulting OLC assembled contigs are locally aligned to the reference sequence to annotate the position of ITDs. ITD Assembler was run on The Cancer Genome Atlas (TCGA) acute myeloid leukemia (AML) dataset, and FLT3-ITD detection rates were compared against orthogonal algorithms. ITD Assembler identified the highest percentage of TCGA FLT3-ITDs, reported significantly higher allele fractions, and discovered additional ITDs in the KIT, CEBPA and WT1 cancer genes. Citation Format: Oliver A. Hampton, Navin Rustagi, Jie Li, Liu Xi, Richard A. Gibbs, Sharon E. Plon, Marek Kimmel, David A. Wheeler. ITD Assembler: An algorithm for internal tandem duplication discovery from short-read sequencing 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 4856. doi:10.1158/1538-7445.AM2015-4856
Faster Registration on International Donor Registries and Shorter Time to Allogeneic Hematopoietic Stem Cell Transplantation After Having Found a Donor Confers Better Outcome In Acute Leukemia Patients
Authors: Mauricette Michallet, Mohamad Sobh, Stephane Morisset, Xavier Thomas, Youcef Chelghoum, Helene Labussiere, Franck E Nicolini, Sophie Ducastelle, Fiorenza Barraco, Nathalie Tedone, Jihane Fatoum, Marie Detrait, Sylvie Rey, Valerie Dubois
Journal: Blood (2010)
Creating Local Learning Health Systems
Authors: William E. Smoyer, Peter J. Embi, Susan Moffatt-Bruce
Journal: JAMA (2016)

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