tbuckley/cabot-search huggingface dataset:
Abstract 3149: An assay quantifying pro-peptides of type XI collagen (PRO-C11) in serum provides novel insight into the pathology of non-small cell lung cancer (NSCLC)
Authors: Nicholas Willumsen, Stephanie N. Kehlet, Tina M. Jensen, Neel I. Nissen, Morten A. Karsdal
Journal: Cancer Research (2020)

Abstract Background: The tumor microenvironment (TME) is characterized by an extensive number and activity of cancer-associated fibroblasts (CAFs). CAFs are the most abundant cell type in the TME of stroma-rich tumors and dictate patient outcome. One of the most specific CAF genes is COL11A1 which encodes the α1-chain of type XI collagen. Type XI collagen is synthesized as a pro-collagen and proteolytically cleaved by bone-morphogenetic protein 1 (BMP-1) to yield mature type XI collagen. Cleaved pro-peptides released to the circulation could serve as biomarkers of type XI collagen formation and provide novel insight into patients with cancer. We developed and evaluated an assay targeting the N-terminal pro-peptide of type XI collagen for quantifying this specific fragment in the circulation (serum) of patients with non-small cell lung cancer (NSCLC). Methods: A monoclonal antibody was raised against the C-terminal neo-epitope on the N-terminal pro-peptide of type XI collagen and employed in the development of a competitive ELISA (PRO-C11). PRO-C11 was measured in serum from 40 stage 3+4 NSCLC patients and compared to 32 age-matched healthy controls. PRO-C11 was correlated with demographic and clinical characteristics (age, BMI, smoking, metastasis, histological subtype). Results: The PRO-C11 assay is technically robust with specificity only for the BMP-1 generated type XI collagen pro-peptide neo-epitope. PRO-C11 was significantly elevated in NSCLC compared to age-matched healthy controls (p&amp;lt;0.0001). No correlation (Pearson, p&amp;gt;0.05) was seen between PRO-C11 and age, BMI, smoking status, metastasis (y/n) and histological subtype (squamous cell carcinoma vs. adenocarcinoma). Conclusion: The present study validates a new serological assay quantifying the pro-peptide of type XI collagen. The biomarker has promising potential for NSCLC and warrants further investigations into stroma-rich cancers. Further studies are needed to evaluate the diagnostic/prognostic use of PRO-C11 in NSCLC. Citation Format: Nicholas Willumsen, Stephanie N. Kehlet, Tina M. Jensen, Neel I. Nissen, Morten A. Karsdal. An assay quantifying pro-peptides of type XI collagen (PRO-C11) in serum provides novel insight into the pathology of non-small cell lung cancer (NSCLC) [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 3149.
Abstract 4740: Molecular profiling of adenoid cystic carcinomas
Authors: Michelle Ellis, Jeff Swensen, Phillip Stafford, Zoran Gatalica
Journal: Cancer Research (2020)

Abstract Introduction: Adenoid cystic carcinomas (AdCC) are uncommon malignant neoplasm that can occur in different locations throughout the body. These tumors are typically characterized by the presence of MYB:NFIB or MYBL1:NFIB fusion, but not in every case. Methods: We analyzed 107 adenoid cystic carcinomas from various primary sites that were genetically profiled using a large NGS panel (592) genes in genomic DNA and whole transcriptome sequencing. Immunohistochemical staining was performed for PD-L1. Results: The primary sites included salivary gland (60), lung (15), sino-nasal passages (10), oral cavity (9) breast (5), head, face or neck or other sites (5), skin (1), vulva (1), and unknown primary site (1). Fusions were detected in 87 cases (81%). The two fusions known to be associated with AdCC, MYB:NFIB and MYBL1:NFIB, were detected in 67 specimens (56 MYB:NFIB, 11 MYBL1:NFIB). In addition several fusions of uncertain significance involving these genes were detected (each found in one sample): MYBL1:SGK3, CD274:NFIB, NFIB:AHI1, NFIB:LINC00271 and TOP2B:MYBL1. No fusions were detected in 20 AdCC; the most common primary sites being salivary glands (14) and lung (4). The most common mutations detected in genomic DNA from these specimens involved NOTCH1 (5 cases), KDM6A (4 cases) ARID1A and TP53 (3 cases each). Two lung primaries were PD-L1 positive, low expression. No pathogenic mutations were detected in 3 cases: 2 salivary gland tumors and 1 oral cavity tumor. In cases with MYBL1:NFIB fusion, the gene expression of MYB is in the lower 20th percentile (relative to the entire cohort) while MYBL1 expression is in the upper 80th percentile. Conversely in cases with the MYB:NFIB fusions, MYB expression is ectopic resulting in expression in the upper 80th percentile while MYLB1 in the lower 20th percentile. Conclusion: We detected a classic MYB:NFIB or MYBL1:NFIB fusion in 67 of 107 adenoid cystic carcinomas profiled in this study. There is a strong pattern linking the presence or absence of fusions with the expression of MYB and MYBL1. Thus, fusions are driving high expression of either MYB or MYBL1, but the gene not involved in the fusion shows evidence of reduced expression. We hypothesize that a negative feedback mechanism may result in reduced expression of the other MYB-family gene to maintain homeostasis. From the treatment perspective, rare primary lung AdCC are amenable for I-O therapy based on expression of PD-L1. Citation Format: Michelle Ellis, Jeff Swensen, Phillip Stafford, Zoran Gatalica. Molecular profiling of adenoid cystic carcinomas [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 4740.
TRIM24-RIP3 axis perturbation accelerates osteoarthritis pathogenesis
Authors: Jimin Jeon, Hyun-Jin Noh, Hyemi Lee, Han-Hee Park, Yu-Jin Ha, Seok Hee Park, Haeseung Lee, Seok-Jung Kim, Ho Chul Kang, Seong-il Eyun, Siyoung Yang, You-Sun Kim
Journal: Annals of the Rheumatic Diseases (2020)

Recently, necroptosis has attracted increasing attention in arthritis research; however, it remains unclear whether its regulation is involved in osteoarthritis (OA) pathogenesis. Since receptor-interacting protein kinase-3 (RIP3) plays a pivotal role in necroptosis and its dysregulation is involved in various pathological processes, we investigated the role of the RIP3 axis in OA pathogenesis.Experimental OA was induced in wild-type or Rip3 knockout mice by surgery to destabilise the medial meniscus (DMM) or the intra-articular injection of adenovirus carrying a target gene (Ad-Rip3 and Ad-Trim24 shRNA). RIP3 expression was examined in OA cartilage from human patients; Trim24, a negative regulator of RIP3, was identified by microarray and in silico analysis. Connectivity map (CMap) and in silico binding approaches were used to identify RIP3 inhibitors and to examine their direct regulation of RIP3 activation in OA pathogenesis.RIP3 expression was markedly higher in damaged cartilage from patients with OA than in undamaged cartilage. In the mouse model, adenoviral RIP3 overexpression accelerated cartilage disruption, whereas Rip3 depletion reduced DMM-induced OA pathogenesis. Additionally, TRIM24 knockdown upregulated RIP3 expression; its downregulation promoted OA pathogenesis in knee joint tissues. The CMap approach and in silico binding assay identified AZ-628 as a potent RIP3 inhibitor and demonstrated that it abolished RIP3-mediated OA pathogenesis by inhibiting RIP3 kinase activity.TRIM24-RIP3 axis perturbation promotes OA chronicity by activating RIP3 kinase, suggesting that the therapeutic manipulation of this pathway could provide new avenues for treating OA.
Abstract 473: Preclinical model of radiation induced lymphopenia to identify abrogation strategies to enhance cancer therapy
Authors: Amrish Sharma, Shinya Neri, Bhanu P. Venkatesulu, Steven H. Lin
Journal: Cancer Research (2020)

Abstract Radiation induced lymphopenia (RIL) is a common and yet often ignored side effect of radiation therapy that has been observed for over 100 years. Numerous studies have demonstrated the correlation between RIL and inferior overall survival outcomes in nearly all cancer types that are treated with radiation therapy. To assess the causative link between RIL and poor disease outcomes, as well as its impact on therapy response, we have developed a mouse model of RIL. Using cone beam CT based image-guided radiation targeting the mid-thorax, we showed that conventionally fractionated radiation of 2 Gy x 5 fractions caused severe and sustained lymphopenia in both C57BL/6 (Th1) and BALB/c (Th2). Increasing the radiation dose and radiation field resulted in more pronounced RIL. Enlarging the volume to include the spleen along with the thorax resulted in greater than 90% elimination of circulating lymphocytes (CD8/CD4/CD19/NK cells). However, radiation to the head resulted in only minimal lymphodepletion suggesting site specific susceptibility to the development of severe RIL. The severity of the lymphodepletion was also unperturbed by rate of blood flow as the administration of varying anesthetics that caused 5 fold differences in heart rate did not alter the severity of RIL. Functionally, RIL abrogated the immunotherapeutic effectiveness of anti-CTLA4 mAb as lymphopenic mice bearing CT26 tumors had complete lack of response to anti-CTLA4 treatment as compared to its control littermates. Similarly, animals treated with radiotherapy had nearly complete amelioration of radiotherapy effectiveness in the setting of severe RIL. However, exogenous administration of IL-15 super agonist (IL-15 SA) (IL-15 and IL-15Rα-Fc) therapy replenished cytotoxic CD8+ T killer cells and natural killer cells to control levels which restored the tumoricidal effect of radiation therapy. Taken together our study have generated the evidence for the causative link between RIL and poorer disease outcomes and presented a potential therapeutic strategy to overcome the adverse effect of RIL. Citation Format: Amrish Sharma, Shinya Neri, Bhanu P. Venkatesulu, Steven H. Lin. Preclinical model of radiation induced lymphopenia to identify abrogation strategies to enhance cancer therapy [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 473.
Abstract 1972: The significance of liquid biopsy in colorectal cancer via GeneReader NGS Systems
Authors: Cem Mujde, Abdullah Hanta, Ozge Sonmezler, Ahmet Rencuzogullari, Ibrahim Boga, Atil Bisgin
Journal: Cancer Research (2020)

Abstract Background: In terms of precision medicine, not only tumoral tissue samples but also with liquid biopsy for somatic variants detection, have been used routinely. It also helps to overcome the resampling difficulties that require an invasive procedure with the problem of tumor heterogeneity. With the Next Generation Sequencing (NGS) method which is accepted as the gold standard in molecular genetic testing, colorectal cancer patients ccfDNA (Circulating Cell-Free DNA) samples were next generation sequenced via a targeted multigene panel. Methods: In our study, liquid biopsy samples of 63 colorectal cancer patients whom referred to Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center) were sequenced via GeneReader NGS Systems (Qiagen). The multi-gene panel which includes cancer related actionable 11 genes (KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, ERBB3, ESR1 and RAF1) were used to identify the variants of drug sensitivity and resistance. Sequencing data were analyzed by QCI-Analyze and QCI-Interpret bioinformatics tools. Results: Forty-three clinically significant variants detected in 53.96% (n=34) of 63 patients. Total of 43 clinically significant variants in 7 genes (KRAS, NRAS, KIT, BRAF, EGFR, PDGFRA and ERBB2) were detected according to the ACMG (American College of Medical Genetics) and AMP (Association for Molecular Pathology) criteria in which 13.95%, 41.86% and 41.86% prospectively related to drug resistance, treatment sensitivity, and both treatment sensitivity and drug resistance. Moreover, 2.33% were classified as uncertain clinical significance due to data mining. Variants detected upon gene names were listed in Table 1. Table 1:Genes and variants distribution in colorectal cancer patientsGene NameVariantsTotal %KRASp.G12A,p.G12C,p.G12D,p.G12V,p.G13S,p.G15S,p.A18V,p.I21M,p.A59T,p.A146T32.56KITp.M541L20.93BRAFp.T559I,p.V600E,p.K601R,p.R603*,p.P632S,p.639I20.93EGFRp.E282K,p.H773R,p.H773P,p.V834A,p.G863D11.63PDGFRAp.E241A,p.Y555H4.65NRASp.G13C,p.E31V,p.Q61R6.98ERBB2p.P1170V2.33 Conclusion: In terms of identifying potential target therapy options without the need of a invasive intervention becomes available with NGS multigene panel studies within high reliability that also have an effect on the quality of life in colorectal cancer patients. Citation Format: Cem Mujde, Abdullah Hanta, Ozge Sonmezler, Ahmet Rencuzogullari, Ibrahim Boga, Atil Bisgin. The significance of liquid biopsy in colorectal cancer via GeneReader NGS Systems [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 1972.
Abstract 6061: NR2F1 limits dissemination of early cancer mammary epithelial cells
Authors: Maria Soledad Sosa, Nupura Kale, Nitisha Shrivastava, Carolina Rodriguez-Tirado, Maria Carlini, Jiayi Ji, Javier Bravo-Cordero
Journal: Cancer Research (2020)

Abstract Cancer cells have been found to disseminate during very early and sometimes asymptomatic stages of tumor progression. At secondary organs, early disseminated cancer cells (eDCCs) can enter a non-proliferative state for prolonged periods of time. Intriguingly, eDCCs also carry metastasis- initiating capacity. However, the mechanisms by which these early cancer cells complete all steps of metastasis including metastasis-initiating capacity are unknown. Here we report that the orphan nuclear receptor and lineage commitment regulator NR2F1 serves as an early barrier to early dissemination propelled by HER2 signaling. NR2F1 loss of function in HER2 early cancer cells induced cell motility, loss of E-cadherin junctions, disorganized laminin-V deposition, decreased β-catenin membrane localization and increased micro-invading cells with CK14+/CK18 phenotype. Importantly, upon NR2F1 depletion in HER2 early cancer acini, TWIST, ZEB1 and PRRX1 levels were upregulated. Our findings reveal a previously unrecognized function of NR2F1 as a suppressor of dissemination during early stages of breast tumor progression. Thus, therapies that restore and activate NR2F1 function might limit early dissemination and metastatic outgrowth. Citation Format: Maria Soledad Sosa, Nupura Kale, Nitisha Shrivastava, Carolina Rodriguez-Tirado, Maria Carlini, Jiayi Ji, Javier Bravo-Cordero. NR2F1 limits dissemination of early cancer mammary epithelial cells [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 6061.
Advances and novel developments in molecular allergology
Authors: Öykü Üzülmez, Tanja Kalic, Heimo Breiteneder
Journal: Allergy (2020)

The continuous search for new allergens and the design of allergen derivatives improves the understanding of their allergenicity and aids the design of novel diagnostic and immunotherapy approaches. This article discusses the recent developments in allergen and epitope discovery, allergy diagnostics and immunotherapy. Structural information is crucial for the elucidation of cross-reactivity of marker allergens such as the walnut Jug r 6 or that of nonhomologous allergens, as shown for the peanut allergens Ara h 1 and 2. High-throughput sequencing, liposomal nanoallergen display, bead-based assays, and protein chimeras have been used in epitope discovery. The binding of natural ligands by the birch pollen allergen Bet v 1 or the mold allergen Alt a 1 increased the stability of these allergens, which is directly linked to their allergenicity. We also report recent findings on the use of component-resolved approaches, basophil activation test, and novel technologies for improvement of diagnostics. New strategies in allergen-specific immunotherapy have also emerged, such as the use of virus-like particles, biologics or novel adjuvants. The identification of dectin-1 as a key player in allergy to tropomyosins and the formyl peptide receptor 3 in allergy to lipocalins are outstanding examples of research into the mechanism of allergic sensitization.
Abstract 6570: Predicting drug effects on breast cancer cell shapes by converging image and transcriptomic profiles
Authors: Zheng Yin, Chris Bakal, Stephen T. Wong
Journal: Cancer Research (2020)

Abstract Cell shapes have long served as hallmarks for cancer diagnostics and therapeutics evaluations. This work converges public available image and transcriptome profiles to build a drug-gene-shape networks, thus facilitate the usage of cell shape features as drug targets during the development of novel cancer therapeutics. We took advantage of a previous work (Sailem et. al., 2017) of image-omits modeling where 504 shape-correlated genes were identified for 20 cell shape features across 18 breast cancer cell lines. Transcriptome profiles from Broad Institute Clue.io database were used to identify small molecular compounds that can significantly impact those shape-correlated genes. As a result, 22 compound families of at least two members were identified as candidates that can significantly impact the shape-correlating gene sets for 13 shape features. Our work re-opens the doors for using cell shape as drug target and considering the impact on cell shapes during drug repurposing and design of combination therapies for breast cancer. Compound families with the most significant correlations with gene sets regulating average cell areaCompound famileAverage scoremTOR inhibitors94.975Tubulin inhibitors94.615Adrenergic receptor antagonist94.545PKC inhibitor-93.580MEK inhibitor-94.137HDAC inhibitor-94.153 Citation Format: Zheng Yin, Chris Bakal, Stephen T. Wong. Predicting drug effects on breast cancer cell shapes by converging image and transcriptomic profiles [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 6570.
Abstract 2932: CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma
Authors: Tian Lan, Hong Wu
Journal: Cancer Research (2020)

Abstract Little success has been achieved in the exploitation of effective interventions against hepatocellular carcinoma (HCC) pathogenesis. To determine the crucial regulators in this process, CD59 was identified from the lung metastasis screening mice models that we previously reported. It is well known that CD59, belonging to membrane-bound complement regulatory proteins (mCRPs), acts as a suppressor of the formation of the membrane attack complex to enable tumor cells to escape from complement surveillance. Apart from that, our work identified CD59 as a potential oncogenic driver in hepatocarcinogenesis and metastasis. Specifically, CD59 was considerably upregulated in HCC tissues. High expression of CD59 was associated with poor overall survival and disease-free survival. Functional studies demonstrated that CD59 knockdown inhibited proliferation, cell cycle and apoptosis resistance of HCC cells, impaired their tumorigenic and metastasis capacities in vitro and in vivo, whereas overexpression of CD59 exhibited opposite cell phenotypes. Mechanistically, CD59 competitively binds to aminoacyl tRNA synthetase complex interacting multifunctional protein 1 (AIMP1), resulting in the disassociation of AIMP1 from Smad-specific E3 ubiquitin protein ligase 2 (Smurf2) and the continuous interaction between Smurf2 and Smad7, thus accelerating the ubiquitin-mediated degradation of Smad7. By contrast, loss of CD59 promoted excessive Smad7 formation, leading to the abolishment of Smad2/3 phosphorylation and subsequent nuclear translocation, therefore inhibiting hepatocarcinogenesis and metastasis. Overall, our findings indicated that CD59 facilitated HCC pathogenesis via modulating TGF-β signaling, apart from disturbing the complement-dependent cytotoxicity. CD59 may be an effective prognostic biomarker and potential therapeutic target for HCC. Citation Format: Tian Lan, Hong Wu. CD59 facilitates tumor progression through activating TGF-β/Smad signaling pathway in hepatocellular carcinoma [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 2932.
Abstract 5855: The genomic landscape of Mongolian hepatocellular carcinoma
Authors: Julián Candia, Enkhjargal Bayarsaikhan, Mayank Tandon, Anuradha Budhu, Marshonna Forgues, Justin Lack, Ann Chao, Jigjidsuren Chinburen, Xin W. Wang
Journal: Cancer Research (2020)

Abstract Mongolia has the highest incidence of-and mortality from- hepatocellular carcinoma (HCC) in the world, which is between three and seven times higher than that observed in other high-incidence populations, such as South Korea, Thailand, and China. In Mongolia, where cancer is the second most common cause of death accounting for nearly a fifth of deaths, HCC is the most prevalent cancer type at about 40% of all cancers. Despite the daunting proportion of this longstanding health crisis, the molecular landscape of Mongolian HCC has not been studied yet. Filling this gap, we aim to identify robust molecular subclasses and driver features informative of the etiology and progression of the disease. Here, we describe molecular characteristics of 76 Mongolian HCC patients by whole-exome and whole-transcriptome sequencing. We present a comprehensive comparison of mutational signatures, driver genes and molecular subtypes of Mongolian HCC versus 373 HCC patients of different ethnicities and diverse etiologies. Mongolian HCC consists of several similar prognostic molecular subtypes in patients from other areas of Asia, Europe and North America as well as several unique types, suggesting potentially the presence of unique etiologies linked to Mongolian patients. Consistently, Mongolian HCC exhibits several common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analyses but also a unique driver (SPTA1) that may be linked to hepatitis D viral infection. Furthermore, unique hotspot missense mutations were identified in driver genes GTF2IRD2B and PNRC2. These results indicate the existence of novel molecular mechanisms at play in Mongolian hepatocarcinogenesis. Citation Format: Julián Candia, Enkhjargal Bayarsaikhan, Mayank Tandon, Anuradha Budhu, Marshonna Forgues, Justin Lack, Ann Chao, Jigjidsuren Chinburen, Xin W. Wang. The genomic landscape of Mongolian hepatocellular carcinoma [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 5855.