tbuckley/cabot-search huggingface dataset:
Abstract 4897: Genome-wide structural variation analysis and characterization of Hepatitis B Virus integration sites in hepatocellular carcinomas using Bionano Genomics whole genome imaging
Authors: Karl Hong, Camille Péneau, Quentin Bayard, Sandrine Imbeaud, Andy Pang, Alex Hastie, Eric Letouzé, Jessica Zucman-Rossi
Journal: Cancer Research (2020)

Abstract Large genomic rearrangements are known contributors to cancer formation. Hepatitis B virus (HBV) integration is a frequent driver of hepatocellular carcinoma, frequently associated with genomic rearrangements. Next generation sequencing (NGS) is commonly used to study these integration sites and rearrangements; however, due to short read lengths, NGS is often unable to characterize large and complicated genomic rearrangements. To solve this problem, whole genome imaging was used to perform genome-wide detection of large structural variants (SVs) in DNA extracted from liver tumors, including characterization of HBV viral integration sites and nearby rearrangements. Ultra-high molecular weight DNA was extracted from liver tissue of four patients diagnosed with hepatocellular carcinoma. The DNA was fluorescently labeled at the motif CTTAAG, linearized, and imaged in nanochannel arrays using a Bionano Genomics Saphyr platform. Images of molecules were converted into digital single-molecule reads. 400X coverage of DNA molecules at least 150 kbp in length was collected for each sample. For three of the patients, somatic structural variants (SV) were identified by comparing SV calls and single molecule DNA reads of liver tumor resections against those of matching physiologically normal liver tissue. For the fourth patient, putative somatic SVs were identified by comparing SV calls against a database of 59,490 known variants from 57 physiologically normal individuals. Among the matched-pair samples, 511 large tumor-unique structural variants were identified. For the fourth sample, 619 putative somatic events were identified. HBV viral integration sites, which had previously been identified via NGS, and nearby SVs were characterized. Complex SVs were resolved, including translocation events with several loci. These findings demonstrate the utility of whole genome imaging for studying the relationship between viral integration and cancer. Citation Format: Karl Hong, Camille Péneau, Quentin Bayard, Sandrine Imbeaud, Andy Pang, Alex Hastie, Eric Letouzé, Jessica Zucman-Rossi. Genome-wide structural variation analysis and characterization of Hepatitis B Virus integration sites in hepatocellular carcinomas using Bionano Genomics whole genome imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4897.
Endoscopic neck dissection using peroral endoscopic myotomy for removal of extraluminal neck foreign body migrated out from the upper esophagus
Authors: Sherif Andrawes, Praneet Wander, Adam Lackey, Arvind J. Trindade, Petros C. Benias
Journal: Endoscopy (2020)

A 50-year-old woman presented to the emergency room with a chief complaint of a foreign body sensation after eating steak prepared on a grill. A soft-tissue radiograph of the neck revealed a linear opacity at the level of the upper esophagus (C6 – C7). A computed tomography (CT) scan of the neck was done, which showed a linear opacity between the upper esophagus and the trachea. An upper gastrointestinal endoscopy was performed, but revealed no foreign body present in the lumen of the esophagus. Under fluoroscopy guidance, the linear opacity was visualized at the level of C6 – C7. An endoscopic ultrasound (EUS) was performed, as has been done in other cases for foreign body identification [1], and it revealed that the foreign body was present outside the muscularis propria of the esophagus. EUS-guided fine-needle aspiration (FNA) removal using a through-the-needle forceps was attempted, but was unsuccessful.
Conditioned medium-electrospun fiber biomaterials for skin regeneration
Authors: Lu Chen, Liying Cheng, Zhen Wang, Jianming Zhang, Xiyuan Mao, Zhimo Liu, Yuguang Zhang, Wenguo Cui, Xiaoming Sun
Journal: Bioactive Materials (2020)

Conditioned medium (CM) contains variety of factors secreted by cells, which directly regulate cellular processes, showing tremendous potential in regenerative medicine. Here, for the first time, we proposed a novel regenerative therapy mediated by biodegradable micro-nano electrospun fibers loaded with highly active conditioned medium of adipose-derived stem cells (ADSC-CM). ADSC-CM was successfully loaded into the nanofibers with biological protection and controllable sustained-release properties by emulsion electrospinning and protein freeze-drying technologies. In vitro, ADSC-CM released by the fibers accelerated the migration rate of fibroblasts; inhibited the over proliferation of fibroblasts by inducing apoptosis and damaging cell membrane; in addition, ADSC-CM inhibited the transformation of fibroblasts into myofibroblasts and suppressed excessive production of extracellular matrix (ECM). In vivo, the application of CM-biomaterials significantly accelerated wound closure and improved regeneration outcome, showing superior pro-regenerative performance. This study pioneered the application of CM-biomaterials in regenerative medicine, and confirmed the practicability and significant biological effects of this innovative biomaterials.
Abstract 858: PrismML: A machine learning platform to query genotype-phenotype patterns in large genomics studies
Authors: Anupama Reddy, Daisy Flemming, Sara Selitsky, Ana Brandusa Pavel, Gabriela Alexe, Gyan Bhanot
Journal: Cancer Research (2020)

Abstract Background: Large-scale genomics studies (e.g. AACR Project GENIE, TCGA, TopMed) have sequenced thousands of patients in an attempt to understand disease associated genomic variables and their clinical correlates. Existing online platforms (e.g. cBioPortal) enable simple gene-based queries, but do not allow more complex modeling to understand disease pathogenesis, risk and outcome. There is an urgent need to build an interactive, modular and scalable platform that enables users to perform multivariate machine learning on existing genomic data. Results: We have built a platform, PrismML, that enables a user to interactively query a dataset, and to run a multitude of machine learning tools, from simple statistical tests for differential analysis to multivariate modeling to predict clinical response, or mortality-risk. Since machine learning models are computationally intensive, we have used the power of cloud computing to make the analyses faster and scalable. Key feature of our platform are: (1) availability of extensive statistical and machine learning methods; (2) implementation of best practices for machine learning, e.g. cross-validation; (3) graphical querying of results to understand the interplay among features. Users can choose to analyze existing data/studies, or upload their own data. Examples of possible queries: “identify genomic features that distinguish metastasis from primary tumors, either in a single cancer or pan-cancer”, or, “build a machine learning model to predict survival within ER- breast cancer patients”. In addition, there is also an acute need to integrate the knowledge extracted from the multitude of data types. To this end, we have integrated multiple data types into gene-scores, and have incorporated known biological/functional information by integrating gene-scores into pathway-scores. Summary: PrismML is an interactive and flexible platform to bring the power of machine learning and statistical modeling to the genomics community. This is an active area of development with multiple ongoing features, such as integrating multiple datasets to increase statistical power in rare diseases, and to enable subsetting large diseases to identify prognostic features. Citation Format: Anupama Reddy, Daisy Flemming, Sara Selitsky, Ana Brandusa Pavel, Gabriela Alexe, Gyan Bhanot. PrismML: A machine learning platform to query genotype-phenotype patterns in large genomics studies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 858.
Abstract 3024: Relationship between venetoclax concentrations and undetectable MRD in patients with chronic lymphocytic leukemia
Authors: Sathej Gopalakrishnan, Rajeev Menon, Brenda Chyla, Divya Samineni, Amanda Jacobson, Su Young Kim, Sven Mensing, Ahmed Hamed Salem
Journal: Cancer Research (2020)

Abstract Minimal residual disease (MRD) is an important clinical endpoint in chronic lymphocytic leukemia (CLL) because it correlates with progression free survival and overall survival. The objective of this work is to investigate the impact of venetoclax (VEN) exposures on undetectable MRD rates in blood and bone marrow (BM) in relapsed/refractory (R/R) CLL patients receiving VEN monotherapy or combination therapy with rituximab (RTX). Data from a total of 708 patients from four VEN monotherapy studies and one combination Phase 1b study (VEN + 6-9 cycles of RTX) in R/R CLL patients were utilized to perform this analysis. The median number of prior therapies in these studies was 3, 42% of the patients had 17p chromosomal deletion and 28% had prior B-Cell Receptor inhibitor (BCRi) therapy. Blood and BM MRD assessments were available for 70% and 38%, respectively, of patients included in the analysis. Absence of an MRD measurement was assumed as detectable MRD for the purposes of this analysis. The average concentration (Cavg) of VEN was computed for each patient by fitting a population pharmacokinetic model to the observed VEN concentration data. The model was used to calculate area under the curve and compute Cavg accounting for VEN dose ramp-ups, reductions and interruptions. The relationships between venetoclax Cavg and undetectable MRD rates were assessed by using quartile plots. Logistic regression analyses were also conducted to quantify the exposure-response relationship. With VEN monotherapy, the undetectable MRD rates in blood and BM increased with the increase in VEN exposures. With VEN + RTX combination treatment, the undetectable MRD rates in blood and BM showed an increase with increasing VEN average concentration, but the benefit saturated with limited increase at exposures beyond 400mg. Logistic regression analyses indicated statistically significant (p&amp;lt;0.01) relationships between VEN average concentrations and undetectable MRD rates in both blood and BM. These results demonstrate that higher venetoclax concentrations are associated with higher undetectable MRD rates in both blood and BM. When VEN is combined with RTX, an increase in VEN dose beyond 400mg is unlikely to result in higher undetectable MRD rates. Citation Format: Sathej Gopalakrishnan, Rajeev Menon, Brenda Chyla, Divya Samineni, Amanda Jacobson, Su Young Kim, Sven Mensing, Ahmed Hamed Salem. Relationship between venetoclax concentrations and undetectable MRD in patients with chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3024.
Abstract LB-062: A live-cell, protein-protein interaction assay identified inhibitors of KRAS4b-G12D interaction with full-length RAF1
Authors: John Columbus, Thomas J. Turbyville, Vanessa Wall, Dominic Esposito, David A. Barda, Sheng-Bin Peng
Journal: Cancer Research (2020)

Abstract KRAS4b is a major driver of cancers of the pancreas, lung, and colon, and until recently was considered undruggable. However, recent discoveries have revealed that molecules can target KRAS directly, and that our understanding of KRAS is incomplete. To exploit this new appreciation of KRAS druggability and biology, we have developed several protein-protein interaction (PPI) assays to target KRAS activity in live cells. Here we report on a campaign where we screened a 20,000-compound library against full length KRAS4b-G12D and RAF1 interactions in live HEK293 cells using the NanoBRET platform. From the list of screening hits, we identified several structurally related active compounds with dose-dependent, albeit weak, inhibition of the PPI signal. We expanded these active compounds to a more complete list of structural analogs which we tested in a full dose response. From this expanded group of compounds, we identified several with low µM IC50s. Follow up with these compounds in secondary assays revealed promising biological readouts, including inhibition of downstream pERK levels in G12D mutant PANC1 cells. In summary, by using well-designed live cell assays, we have identified promising leads, which we are pursuing with mechanism of action studies. Citation Format: John Columbus, Thomas J. Turbyville, Vanessa Wall, Dominic Esposito, David A. Barda, Sheng-Bin Peng. A live-cell, protein-protein interaction assay identified inhibitors of KRAS4b-G12D interaction with full-length RAF1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-062.
Abstract 5651: JNJ-61186372, an Fc enhanced EGFR/cMet bispecific antibody, mediates EGFR and cMet downmodulation and therapeutic efficacy preclinically through monocyte / macrophage mediated trogocytosis
Authors: Smruthi Vijayaraghavan, Lorraine Lipfert, Barbara Bushey, Kristen Chevalier, Benjamin Henley, Ryan Lenhart, Marilda Beqiri, Hillary J. Millar, Kathryn Packman, Matthew V. Lorenzi, Sylvie Laquerre, Sheri Moores
Journal: Cancer Research (2020)

Abstract Small molecule inhibitors targeting EGFR are now standard of care in NSCLC patients harboring EGFR mutations, but acquired resistance invariably develops through secondary mutations within EGFR and/or through activation of compensatory pathways such as cMet. JNJ-61186372 (JNJ-372) is an anti-EGFR and cMet bispecific antibody with enhanced binding to immune cell Fcγ receptors, designed to target tumors with activated EGFR and cMet signaling through a distinct mechanism of action. Ongoing first-in-human study in patients with advanced, treatment refractory EGFR mutant NSCLC revealed JNJ-372 to have clinical activity in patients with diverse EGFR-mutated NSCLC, including Exon 20 mutations, TKI resistance mutations (T790M, C797S), and resistance due to MET amplification. However preclinically, despite potent anti-tumor activity in NSCLC xenograft models, only modest anti-proliferative effects were observed with JNJ-372 in cell lines in vitro. Interestingly, the addition of isolated human immune cells (PBMCs) to the in vitro assays enhanced JNJ-372-mediated EGFR and cMet downregulation, and dose-dependent tumor cell killing. Through depletion or enrichment of individual immune cell types, we demonstrated that monocytes and/or macrophages are necessary for JNJ-372 Fc interaction-mediated EGFR/cMet downmodulation. Depletion of macrophages in mice showed that they are required for JNJ-372 anti-tumor efficacy. Finally, we showed that the down-modulation of EGFR and cMet receptors occurs through monocyte or macrophage-mediated trogocytosis. Collectively, these results demonstrate a novel Fc-dependent mechanism of action for JNJ-372 and support its continued clinical development in patients with aberrant EGFR and cMet signaling. Citation Format: Smruthi Vijayaraghavan, Lorraine Lipfert, Barbara Bushey, Kristen Chevalier, Benjamin Henley, Ryan Lenhart, Marilda Beqiri, Hillary J. Millar, Kathryn Packman, Matthew V. Lorenzi, Sylvie Laquerre, Sheri Moores. JNJ-61186372, an Fc enhanced EGFR/cMet bispecific antibody, mediates EGFR and cMet downmodulation and therapeutic efficacy preclinically through monocyte / macrophage mediated trogocytosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5651.
Abstract LB-314: Development of reference material guaranteed copy number of DNA for liquid biopsy
Authors: Yusuke Osaki, Yoshiharu Sato, Miho Ishii, Yuki Yonekawa, Ryo Matoba
Journal: Cancer Research (2020)

Abstract cfDNA (cell free DNA) analysis using liquid biopsy plays an important role in cancer research. In particular NGS (next-generation sequencer)-based assay has attracted wide interests, because it can not only screen many cancer genes but also can detect ultra-low-concentration mutations at the same time. However, there is no reference material to evaluate correctly its performance. Currently, most researchers use diluted human genomic DNA that is commercially available as reference, but adjusting its concentration is difficult because of the Poisson distribution. Herein, we have developed a method to dispense cells with counting a cell one by one using inkjet technology (Manabu Seo, et. Al., 2019, Anal. Chem.). By lysing cells after dispensing, the defined copy number of DNA is prepared with a single molecule level. In this study, we assessed the feasibility of our reference material prepared by inkjet as a control for rare mutation detection (e.g. minimal sampling bias and high reproducibility). Spike-in control samples with exact allele frequencies with 0.07%, 0.53%, 0.64%, and 1.0%, were prepared by accurately dispensing with inkjet the cells that contain a sequence of exons 18, 19, 20, and 21 of EGFR. The EGFR sequence has G719A, E746_A750del, T790M, C797S, L858R, and L861Q mutations. For comparison, a few samples were also prepared by manual dilution process. The EGFR mutations were analyzed by the method of high-sensitivity procedure using NGS (Yoji Kukita, et. Al., 2013, PLoS ONE.). Result of the inkjet method had less variation than the manual dilution method, and high repeatability was obtained. Especially in E746_A750del (0.53%) the inkjet samples were tested three times (n = 24 each), and their CVs (coefficient of variation) were 17%, 17%, and 12%. In contrast, the manual sample's one was 33%. In addition, linearity of T790M and L858R were R2 = 0.98 and R2 = 0.96, respectively. The reference material produced by inkjet method can be provided under the same conditions at each facility and make it possible to improve the reliability of liquid biopsy. Therefore, the reference material could be appropriate standard for external quality control for EGFR mutant detection of liquid biopsy. Citation Format: Yusuke Osaki, Yoshiharu Sato, Miho Ishii, Yuki Yonekawa, Ryo Matoba. Development of reference material guaranteed copy number of DNA for liquid biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-314.
THU0081 Amelioration of collagen induced arthritis by thrombin inhibition
Authors: N Busso, I Marty, V Péclat, G Kirdaite, R Salvi, A So
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The deposition of fibrin observed in arthritic joints has been proved to have a deleterious role.<sup>1</sup> <h3>Objectives</h3> We wish to explore the effect of the thrombin inhibitor PEG-hirudin in the pathogenesis of the murine collagen-induced arthritis (CIA). <h3>Methods</h3> CIA was induced in male DBA/1J mice by intradermic injection of native chicken type II collagen. PEG-hirudin (injected subcutaneously at 1 mg/kg or 0.1 mg/kg per day) was given during 16 days, starting 20 days after the first immunisation (preventive treatment) or at the onset of clinical signs of arthritis (curative treatment). <h3>Results</h3> All the mice treated with PEG-hirudin had a significantly prolonged thrombin time compared to control mice. PEG-hirudin, administered in a preventive way, led to significantly reduced incidence and severity of CIA during most of the treatment period, as assessed by clinical scoring. Accordingly, histological features showed a significant diminution of synovial hyperplasia in PEG-hirudin-treated mice compared to untreated mice. There was also a significant down-modulation of the synovial proinflammatory IL-1b and IL-12p35 cytokine mRNAs in treated mice. Intra-articular fibrin, evaluated by immunohistochemistry, was significantly reduced in treated mice compared to control mice and was positively correlated with both clinical and histological scorings. Most importantly, once arthritis was established, there was also a curative effect of PEG-hirudin. <h3>Conclusion</h3> PEG-hirudin prevents the onset of CIA in a dose-dependent manner and has also a curative effect on established arthritis, suggesting that thrombin inhibition may offer a new therapeutic approach in arthritis. <h3>Reference</h3> Busso N, Péclat V, Van Ness K, <i>et al</i>. J Clin Invest. 1998;102:41–50
Genetic variants of GSTM5, SULT1C2 and CYP39A1 and the risk of breast cancer in Caucasians and African-Americans
Authors: Xuemei Zhang, Angie Stone, Qingyi Wei, Li-E Wang, Robert Millikan, Baitang Ning, Susan Kadlubar, Fred Kadlubar
Journal: Cancer Research (2008)

1907  Breast cancer is one of the most frequently occurring cancers and is the major cause of death in women worldwide. Expression and activity of drug metabolizing enzymes play a key role in the etiology of breast cancer, since these enzymes are involved in activation and/or detoxification of xenobiotics including carcinogens. Genetic variations in drug metabolizing genes may alter their enzymatic activity (expression) and in turn vary individuals’ susceptibility to breast cancer. SULT1C2 catalyzes the sulfate conjugation of many compounds and a recent study reported that SULT1C2 Glu5Asp polymorphism was associated with lower acute myeloblastic leukemia relapse rate and increased disease-free survival; GSTM5 belongs to Glutathione S-transferases (GST) family that metabolizes a broad battery of xenobiotics and carcinogens, and a C to T transition at the codon 179 causes Pro to Leu amino acid substitution in GSTM5 protein; CYP39A1 is a member of cytochrome P450 family that plays an important role in xenobiotic activation, and a polymorphism in CYP39A1 leads a Lys to Asn amino acid change in codon 324. We hypothesized that these genetic polymorphisms could contribute to the etiology of breast cancer due to the fact that they change the enzymatic activities of the corresponding enzymes. Therefore, we conducted a case-control study with 1243 cases and 1307 controls in Caucasians and African-Americans. All genotypes were determined by Taqman SNP Genotyping Assays. Logistic regression analysis revealed that a significantly decreased risk of breast cancer is associated with CYP39A1 324 Asn/Asn or 324 Lys/Asn genotype in African-Americans (OR=0.60; 95%CI=0.37-0.96), but not in Caucasians. We also found that the SULT1C2 Glu/Glu carriers had increased breast cancer susceptibility compared to those with Asp/Asp genotype (OR=1.55; 95% CI=1.04-2.30) in Caucasians, but not in African-Americans. Compared to the subjects having GSTM5 179 Leu/Leu genotype, GSTM5 179 Pro/Pro African-American carriers had a lower OR (0.62) for breast cancer, however, without statistical significance (P=0.07). We did not find a significant difference of breast cancer risk for GSTM5 genotypes in Caucasians. These results suggest that these genetic variants in SULT1C2, GSTM5 and CYP39A1 may be associated with altered risk of breast cancer in different ethnic groups.